CN104434925A - Anti-tumor effect enhancer and anti-tumor preparation - Google Patents
Anti-tumor effect enhancer and anti-tumor preparation Download PDFInfo
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- CN104434925A CN104434925A CN201410473526.1A CN201410473526A CN104434925A CN 104434925 A CN104434925 A CN 104434925A CN 201410473526 A CN201410473526 A CN 201410473526A CN 104434925 A CN104434925 A CN 104434925A
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- ftorafur
- lomustine
- gimeracil
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- oteracil potassium
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Abstract
The invention relates to an anti-tumor effect enhancer and an anti-tumor preparation. The anti-tumor effect enhancer is a lipidosome preparation containing an effective dose of lumostine, and can be used for improving the anti-tumor activity of a combined medicine containing effective doses of tegafur, gimeracil and oteracil potassium. Compared with the prior art, the anti-tumor effect enhancer has the advantage of stronger anti-tumor enhancing effect for the combined medicine containing tegafur, gimeracil and oteracil potassium.
Description
Technical field
The present invention relates to antitumor drug technical field, particularly relate to the antitumor effect fortifier comprising lomustine (Lomustine) Liposomal formulation, and comprise the antitumor agent of described Liposomal formulation.
Background technology
Up to now, develop in medical domain and employ a lot of anticarcinogen.Such as, ftorafur (tegafur) is activated in vivo, and progressively discharges activity form, i.e. 5-fluorouracil (being hereafter referred to as " 5-FU "), therefore alleviates toxicity or side effect that 5-FU shows.Combination medicine (trade name: TS-1 containing ftorafur, Gimeracil (gimeracil), Oteracil Potassium (oteracilpotassium) three kinds of medicaments, mol ratio=the 1:0.4:1 of ftorafur/Gimeracil/Oteracil Potassium, Taiho Pharmaceutical Co. Ltd (Taiho Pharmaceutical Co., Ltd.) manufacture, hereafter this combination medicine is referred to as TS-1) there is stronger antitumous effect, because Gimeracil suppresses the degraded of 5-FU.In said preparation, because Oteracil Potassium suppresses the generation of gastrointestinal toxicity specifically, therapeutic effect thus improve, described gastrointestinal toxicity may be that the antitumous effect of the enhancing reached by ftorafur and Gimeracil two kinds of medicaments is adjoint.Therefore, TS-1 contributes to the treatment (No. 2614164th, Japan Patent) of Several Kinds of Malignancy.
But therapeutic agent and the Therapeutic Method with the stronger therapeutic effect being enough to prolongation cancer patient existence are still considered to required.The administering drug combinations chemotherapy (conjoint therapy) of the various medicaments that the mechanism of action of antitumous effect and/or side effect is different from each other attempts to improve therapeutic effect and some conjoint therapies contribute to improving treatment of cancer really.Such as, when lomustine is used alone, show low antitumous effect, therefore use with other drug combination.
Show low antitumous effect when lomustine is used alone, one of reason is that the accumulation of this medicament in tumor tissues is low.When after antitumor agent administration, it can rapidly disappear or be distributed to healthy organ from blood circulation, and therefore, this antitumor agent effectively can not be accumulated in tumor tissues.Therefore, a lot of antitumor agent can not show enough anti-tumor activities always, and their frequent normal tissues have harmful effect (side effect), cause serious toxicity.Strengthen the important goal that effect of antitumor agent is current cancer chemotherapy, and need exploitation badly the medicine of medicine effectively accumulation in tumor can be made to send system (DDS).
Liposome is the closed vesicle of the phospholipid comprised as key component, and its phospholipid is from biomaterial.So to live body administration time, liposome shows hypotoxicity and low antigenicity.In addition, some reports show drug pack can to control in liposome medicine stability in blood and bio distribution, thus its delivery efficiency being effectively carried to target tissue is improved.The known vesicle such as with the liposome of 100-200nm particle diameter is effectively accumulated in tumor, because the new vessels being present in tumor demonstrates relatively high permeability compared with the blood vessel in health tissues.
Chinese invention patent application publication No. CN 103271922A discloses a kind of antitumor effect fortifier of oxaliplatin liposome preparation and comprise the antitumor agent of this Liposomal formulation of comprising, by using the oxaliplatin be encapsulated in Liposomal formulation, the conjoint therapy of the combination medicine that oxaliplatin adds containing ftorafur, Gimeracil, Oteracil Potassium demonstrates the antitumous effect significantly strengthened, and does not increase side effect.
But Liposomal formulation need further raising with the antitumous effect of the conjoint therapy of combination medicine.
Summary of the invention
The object of the present invention is to provide a kind of antitumor effect fortifier comprising the Liposomal formulation of lomustine, and comprising the antitumor agent of described Liposomal formulation, described antitumor effect fortifier is stronger to the antitumor reinforced effects of the combination medicine containing ftorafur, Gimeracil, Oteracil Potassium compared to existing technology.
The present invention includes following content:
In first aspect, the invention provides a kind of antitumor effect fortifier, it is the Liposomal formulation of the lomustine containing effective dose, and it is for improving the anti-tumor activity of the combination medicine of the treatment effective dose containing ftorafur, Gimeracil and Oteracil Potassium.
Preferably, in the lipid components of described Liposomal formulation, at least one is phospholipid;
Preferably, the film surface Polyethylene Glycol of described liposome, polyglycerine or cation lipid are modified.
Preferably, the molar ratio of described lomustine and ftorafur is 0.5-2:1.
Preferably, in the combination medicine of the described treatment effective dose containing ftorafur, Gimeracil and Oteracil Potassium, the Gimeracil of use and the molar ratio of ftorafur are 0.5-2:1, and the molar ratio of the Oteracil Potassium used and ftorafur is 0.5-2:1.
In second aspect, the invention provides a kind of antitumor agent, it comprises the combination of Liposomal formulation and combination medicine, and described Liposomal formulation obtains by being encapsulated in liposome by lomustine, and described combination medicine contains ftorafur, Gimeracil and Oteracil Potassium.
Preferably, in the lipid components of described Liposomal formulation, at least one is phospholipid;
Preferably, the film surface Polyethylene Glycol of described liposome, polyglycerine or cation lipid are modified.
Preferably, the molar ratio of described lomustine and ftorafur is 0.5-2:1.
Preferably, in the combination medicine of the described treatment effective dose containing ftorafur, Gimeracil and Oteracil Potassium, the Gimeracil of use and the molar ratio of ftorafur are 0.5-2:1, and the molar ratio of the Oteracil Potassium used and ftorafur is 0.5-2:1.
Preferably, described antitumor agent consists of test kit, and described test kit comprises Liposomal formulation and combination medicine, and described Liposomal formulation contains lomustine, and described combination medicine contains ftorafur, Gimeracil and Oteracil Potassium.
Preferably, described Liposomal formulation is by intravenous, intraperitoneal, intramuscular or subcutaneous administration, and the combination medicine oral administration containing ftorafur, Gimeracil and Oteracil Potassium.
Beneficial effect of the present invention is: antitumor effect fortifier of the present invention, is the Liposomal formulation of the lomustine containing effective dose, can significantly improve the anti-tumor activity of the combination medicine of the treatment effective dose containing ftorafur, Gimeracil and Oteracil Potassium.Experimental result shows: compared to existing technology, and antitumor effect fortifier of the present invention is stronger to the antitumor reinforced effects of the combination medicine containing ftorafur, Gimeracil, Oteracil Potassium.
Accompanying drawing explanation
Fig. 1 is the conjoint therapy comparison diagram of conjoint therapy with DPPC liposome l-OHP and TS-1 of DPPC liposome lomustine and TS-1;
Fig. 2 is the conjoint therapy comparison diagram of conjoint therapy with HSPC liposome l-OHP and TS-1 of HSPC liposome lomustine and TS-1.
Detailed description of the invention
Below in conjunction with embodiment, embodiment of the present invention are described in detail.It will be understood to those of skill in the art that following examples are only the preferred embodiments of the present invention, so that understand the present invention better, thus should not be considered as limiting scope of the present invention.For a person skilled in the art, the present invention can have various modifications and variations, within the spirit and principles in the present invention all, and any amendment done, equivalent replacement or improvement etc., all should be included within protection scope of the present invention.
Experimental technique in following embodiment, if no special instructions, is conventional method; Experiment material used, if no special instructions, is and is purchased available from routine biochemistry chemical reagent work.
(1) antitumor effect fortifier
The invention provides antitumor effect fortifier to strengthen the anti-tumor activity of the combination medicine for the treatment of effective dose, described combination medicine contains ftorafur, Gimeracil and the Oteracil Potassium for the treatment of effective dose.Antitumor effect fortifier is prepared as Liposomal formulation, and this Liposomal formulation obtains by being encapsulated in by the lomustine being used for the treatment effective dose improving antitumous effect in the liposome that is made up of at least one lipid components.
(1-1) Liposomal formulation
Lomustine is Cell cycle non-specific medicine, to being in G1-S border, or the cells being most sensitive that S is early stage, also there is inhibitory action to the G2 phase, cause the generation of this medicament for the cytotoxicity of cancerous cell.Lomustine can produce according to known method, such as, and method disclosed in Chinese invention patent application publication No. CN 101088563A.
The liposome used in Liposomal formulation of the present invention is the vesicle that formed by the phospholipid disperseed in water and has by the membrane-enclosed inner aqueous phase of fat, and described phospholipid is the main component of cell membrane.Liposome can be divided into three classes according to the number of particle diameter and lipid layer, i.e. multilamellar vesicle: MLV, large unilamellar vesicle: LUV and little unilamellar vesicle: SUV.Any type liposome may be used for the present invention.The liposome used in the present invention needs to have stable form before and after to body administration.The example of phospholipid forming liposome comprises the purification egg PC of hydrogenation, and (phase transition temperature is 50 DEG C, hereafter be called HEPC), (phase transition temperature is about 55 DEG C to the Refined Soybean phosphatidylcholine of hydrogenation, hereafter be called HSPC), (phase transition temperature is about 41 DEG C to dipalmitoyl phosphatidyl choline, hereafter be called DPPC), distearoyl phosphatidylcholine (phase transition temperature is about 58 DEG C, is hereafter called DSPC) and POPC (phase transition temperature is about-3 DEG C).In the middle of these, HEPC, HSPC, DPPC and DSPC are preferred.
In this manual, the purification egg PC of hydrogenation means to be obtained by the hydrogenization of the phosphatidylcholine from egg yolk.An example of the purification egg PC of the hydrogenation used in preferred embodiments comprises the phosphatidylcholine as main component, and its acyl moiety is the C16-18 acyl group from saturated straight chain fatty acid.In the present invention, the purification egg PC of hydrogenation is obtained by the egg PC of purification hydrogenation; Further, such as, those purity are not less than 80% and preferably those purity are not less than the egg PC of the hydrogenation of 90% is available.
In this manual, HSPC means to be obtained by the hydrogenization of the phosphatidylcholine from Semen sojae atricolor.An example of the HSPC used in preferred embodiments comprises the phosphatidylcholine as main component, and its acyl moiety is the C16-18 acyl group from saturated straight chain fatty acid.In the present invention, the Refined Soybean phosphatidylcholine of hydrogenation is obtained by refine HSPC; Further, such as, those purity are not less than 80% and preferably those purity are not less than the HSPC of 90% is available.
These phospholipid can be used alone or two or more conbined usage.By using the phospholipid with different phase transition temperature, the mobility of liposome lipid bilayer can change.This just allows in view of In vivo kinetics after encapsulation rate, stability in pharmaceutical preparation, administration etc. selects most suitable phospholipid.
Except these phospholipid, the liposome used in the present invention preferably mixes with stabilizing agent, such as, it is reported the cholesterol of the stability can improving liposome or derivatives thereof.In addition, if necessary, by with from the part being selected from Polyethylene Glycol, polyglycerine or similar hydrophilic high molecular material, comprise the fat (being hereafter called cation lipid) of amino, amidino groups, guanidine radicals or similar alkaline functional base, or peptide, agglutinin, antibody, saccharide, glycoprotein, glycolipid etc. are modified semicrystalline material, stability in the blood of liposome, tissue distribution, can to improve further to the transitional etc. of tumor tissues.
In the present invention, " Polyethylene Glycol (polyethyleneglycol) " not only comprises unsubstituted Polyethylene Glycol, also comprises the derivant after its lipophilic (hydrophobic) side chain formation covalent bond.The instantiation of lipophilic side chain comprises alkyl chain, phospholipid and cholesterol.The derivant being generally used for the multiple Polyethylene Glycol of the stability improving liposome may be used for the present invention.Similarly, " polyglycerine (polyglycerin) " of the present invention not only comprises unsubstituted polyglycerine, also comprises the derivant that its lipophilic (hydrophobic) side chain forms covalent bond.The instantiation of lipophilic side chain comprises alkyl chain, phospholipid and cholesterol.The multiple polyglycerine derivant being generally used for the stability improving liposome may be used for the present invention.In addition, also can add glycerol, glucose, sodium chloride etc. can add as isotonic agent.In addition, the antiseptic such as benzoates, methaform, benzyl alcohol, propylene glycol.
Liposomal formulation
Liposomal formulation of the present invention can be produced by known method.Example for generation of the known method of Liposomal formulation comprises reverse evaporation (Proc.Natl.Acad.Sci.USA, Vol.75,4194,1978, WO97/48398), freeze-thaw method (Arch.Biochem.Biophys, Vol.212,186,1981), pH gradient method (Biochem.Biophys.Acta, Vol.816,294,1985) etc.
In these methods, when using reverse evaporation, Liposomal formulation of the present invention produces according to following process.Such as, lipid components is dissolved in chloroform, ether, ethanol or similar solvent, and is placed in pear shape bottle by the solute obtained.Solvent, by evaporation under reduced pressure removed, forms lipid membrane.Subsequently, the mixed liquor added containing chloroform and diethyl ether carrys out dissolving films, and the ratio of chloroform/diethyl ether is 1/2.Add the aqueous solution containing activating agent wherein, and mixture is obtained Emulsion in ultrasonic 15 minutes at 25 DEG C.While vortex oscillation, by evaporating one hour in Rotary Evaporators, the organic facies of the Emulsion obtained is removed to change w/o Emulsion into o/w Emulsion.Form liposome and medicament to be thus encapsulated in liposome.Said process allows medicament pack in liposome.
It is reported that the particle diameter of liposome affects bio distribution and tumor accumulation (Biol.Pharm.Bull., Vol.17,935,1994) of its payload strongly.In the present invention, granule sizing is preferably carried out to obtain the liposome that is desirable, consistent size wherein containing medicament.Such as, use biofraction instrument (biodisruptor) (Japan Precise Machine Co., Ltd (Nippon Seiki Co., Ltd.) manufacture, Deng) carry out supersound process or use nanomizer (Jitian's machinery (YoshidaKikaiCo., Ltd.) manufacture) implement high-pressure emulsification etc., the particle diameter of liposome can adjust to the average particulate diameter with about 100-200nm.Alternatively, under nitrogen pressure, use different polycarbonate membrane filter (0.4 μm, 0.2 μm, 0.1 μm and 0.08 μm) that the solution containing liposome is carried out sizing, the particle diameter of liposome can adjust to the average particulate diameter with about 100-300nm.
In the present invention, term " average particulate diameter (average particle diameter) " represents the average particulate diameter using NICOMP370HPL submicron particles analyser (being manufactured by Particle Sizing System company) to be measured by light scattering method.
If desired, by modifying semicrystalline material with Polyethylene Glycol, polyglycerine, cation lipid or part such as peptide, agglutinin, antibody, saccharide, glycoprotein or glycolipid, in the blood of liposome, stability, tissue distribution and tumor-localizing can improve further.
In preferred embodiments, utilize the solution as lomustine solution to produce Liposomal formulation of the present invention, this solution is that lomustine is dissolved in the glucose solution of 1-10% and obtains by the mode by becoming 1-20mg/ml with the concentration of lomustine.
If desired, the Liposomal formulation containing lomustine so obtained can by ultracentrifugation, gel filtration, ultrafiltration and dialysis.These process can suitably be carried out separately or combine carrying out, and remove the medicament be not encapsulated in liposome thus.
The Liposomal formulation containing lomustine obtained by said method can directly be used.But, in view of storage time, condition etc., containing lomustine Liposomal formulation can add excipients as mannitol, trehalose, lactose, glycine after lyophilizing.Alternatively, containing lomustine Liposomal formulation can after adding frozen dose of such as glycerol freezen protective.
In preferred embodiments, the amount of the lomustine that lomustine liposomes preparation contains is 1-50 μ g/mg lipid, and preferably 5-40 μ g/mg lipid.
Liposomal formulation containing lomustine of the present invention has preferably 50-300nm and the average particulate diameter being more preferably 80-200nm.
Liposomal formulation containing lomustine suspends or dilution with the upper acceptable aqueous solution of physiology usually, then uses as ejection preparation (intravenous, intraperitoneal, intramuscular or transdermal formulations); But the Liposomal formulation containing lomustine also can as uses such as oral formulations, nasal drop, inhalant, suppository, transdermal formulation, through mucous membrane absorbable preparations.In the case, according to usual way, use suitable carrier that the Liposomal formulation containing lomustine is formed as preparation compositions.Herein can carrier be conventional those in traditional drug formulations.Its instantiation comprises excipient, binding agent, disintegrating agent, lubricant, coloring agent, flavour enhancer, fumet, surfactant etc.
Described below is the example of the combination medicine containing ftorafur, Gimeracil and Oteracil Potassium, its antitumous effect can be strengthened by antitumor effect fortifier of the present invention.
(1-2) the combination medicine containing ftorafur, Gimeracil and Oteracil Potassium
Ftorafur (common name, the fluoro-1-of chemical name: 5-(2-tetrahydrofuran base)-2,4-(1H, 3H)-hybar X) is known compound, and its release 5-FU that is activated in vivo, namely plays the activity form of anti-tumor activity.Ftorafur can be produced according to known method.
Gimeracil (common name, chemical name: gimeracil) is also known compound, and itself does not represent any anti-tumor activity.But it can suppress the metabolic inactivation of 5-FU in vivo, 5-FU antitumous effect is caused to increase.
Oteracil Potassium (common name, chemical name: 1,2,3,4-tetrahydrochysene-2,4-dioxy-1,3,5-triazines-6-carboxylic acid potassium) be also known compound, although itself does not represent any anti-tumor activity, but it mainly rests in gastrointestinal tract, suppress the activation of 5-FU in gastrointestinal tract, thus stop the disorder of gastrointestinal tract that 5-FU causes.
About containing three kinds of compositions, namely as the combination medicine of the ftorafur of active component, Gimeracil and Oteracil Potassium, the ratio of often kind of active component can in the scope of the description relevant with known pharmaceutical agents.Ratio is usually as following: the ftorafur of every 1 mole, and the usage ratio of Gimeracil is about 0.5-2 mole and preferably about 0.7-1.5 mole, and the usage ratio of Oteracil Potassium is about 0.5-2 mole and preferably about 0.7-1.5 mole.
Can be prepared as the combination medicine of active component the medicament forms comprising two or more medicaments containing ftorafur, Gimeracil and Oteracil Potassium, wherein often kind of medicament contains the combination in any that a kind of described active component or often kind of medicament contain described active component; Or be prepared as the medicament forms comprising single medicament, this medicament contains whole described active component.In either case, according to usual way, use suitable pharmaceutical carrier that this combination medicine is prepared into pharmaceutical composition.Herein can carrier be conventional those in traditional drug formulations, such as excipient, binding agent, disintegrating agent, lubricant, coloring agent, flavour enhancer, fumet, surfactant etc.
When use comprise the combination medicine of the medicament forms of two or more medicaments time, often kind of medicament can administration simultaneously, or a kind of medicament can random time administration before or after other medicament administration.Preferably, the administration simultaneously of all medicaments, or in before or after other medicament administration 4 hours of a kind of medicament, more preferably administration in 2 hours.
(1-3) medication
Above-mentioned antitumor effect fortifier (namely containing the Liposomal formulation of lomustine) can with comprise three kinds of compositions, namely as combination medicine administration or the administration simultaneously respectively of the ftorafur of active component, Gimeracil and Oteracil Potassium, described combination medicine is prepared to unit dosage form.More specifically, antitumor effect fortifier of the present invention can with antitumor agent simultaneously administration or the random time administration before or after antitumor agent administration, described antitumor agent contains three kinds of compositions, and namely ftorafur, Gimeracil and Oteracil Potassium are as active component.Preferably, the administration simultaneously of antitumor effect fortifier and anti-tumor agent, or in before or after anti-tumor agent administration 4 hours, administration in 2 hours preferably before or after anti-tumor agent administration.When given continuously, administration frequency and the delivery time of antitumor agent and antitumor effect fortifier should suitably be selected.
When the Liposomal formulation containing lomustine and the anti-tumor agent administration at the same time or separately containing ftorafur, Gimeracil and Oteracil Potassium three kinds of active component, the dosage of antitumor effect fortifier preferably makes for every 1 mole of ftorafur, the amount of lomustine is about 0.5-2 mole, preferably about 0.7-1.5 mole, more preferably about 1-1.2 mole.
(2) antitumor agent
The invention provides antitumor agent, its antitumor effect fortifier (Liposomal formulation containing lomustine) comprising the combination medicine containing ftorafur, Gimeracil and Oteracil Potassium three kinds of active component and combine with it.Antitumor agent can for comprising the pharmaceutical preparation of various medicaments, and wherein often kind of medicament contains four kinds of above-mentioned compositions, three kinds of namely above-mentioned compositions and the one of liposome containing lomustine, or often kind of medicament contains the combination in any of these compositions; Or antitumor agent can for comprising the medicament forms of single medicament, and this medicament comprises all the components.More specifically, antitumor agent of the present invention can make the one-pack type containing all above-mentioned 4 kinds of compositions, or the multi-pharmaceutics of the medicament comprised containing 1-3 kind composition and one or more medicaments containing all the other compositions.Particularly preferred example is two parts preparations, wherein, containing the medicament of ftorafur, Gimeracil and Oteracil Potassium three kinds of compositions as active component, presents as point other dosage form with the medicament containing the lomustine be encapsulated in Liposomal formulation.
About anti-tumor agent, no matter it is made up of single medicament or multiple medicament, and the ratio of constituent is unrestricted.Usually, to every 1 mole of ftorafur, the usage ratio of Gimeracil is about 0.5-2 mole and preferably about 0.7-1.5 mole; The usage ratio of Oteracil Potassium is about 0.5-2 mole and preferably about 0.7-1.5 mole; And the usage ratio of lomustine is about 0.5-2 mole, preferably about 0.7-1.5 mole, more preferably about 1.0-1.2 mole.Especially, constituent preferred molar ratio is ftorafur: Gimeracil: Oteracil Potassium: lomustine=about 1:1:1:1.When anti-tumor agent is two-form, wherein containing the medicament of ftorafur, Gimeracil and Oteracil Potassium three kinds of compositions as active component with the liposome containing lomustine as above-mentioned point of other dosage form in current, antitumor agent preferably includes combination medicine and pharmaceutical preparation, this combination medicine contains ftorafur, Gimeracil and the Oteracil Potassium that mol ratio is 1:1:1, this pharmaceutical preparation contains lomustine, for every 1 mole of ftorafur, the ratio of lomustine is about 0.5-2 mole, preferably about 0.7-1.5 mole, more preferably about 1.0-1.2 mole.
Can, according to standard method, suitable pharmaceutical carrier be used to be pharmaceutical composition by active fraction preparation.Herein can carrier be conventional those in traditional drug formulations, such as excipient, binding agent, disintegrating agent, lubricant, coloring agent, flavour enhancer, fumet, surfactant etc.
When using having multi-pharmaceutics and comprising the anti-tumor agent of two or more medicaments as described above, often kind of medicament can administration simultaneously, or often kind of medicament can random time administration before or after other medicament administration.Preferably, the administration simultaneously of all medicaments, or in before or after other medicament administration 4 hours of a kind of medicament, more preferably administration in 2 hours.
(3) test kit
The invention provides the test kit comprising the Liposomal formulation containing lomustine and the combination medicine containing ftorafur, Gimeracil and Oteracil Potassium.More specifically, the invention provides the test kit for mammalian cancer treatment, described test kit comprises:
(a) anti-tumor compositions, its contain treatment effective dose ftorafur, for strengthen the effective dose of antitumous effect Gimeracil and for suppressing the Oteracil Potassium of the effective dose of side reaction, (b) Liposomal formulation, it is packaged with the lomustine of the effective dose for strengthening antitumous effect.
The compositions be included in this test kit can for medicament forms known arbitrarily.According to its medicament forms, usually compositions is placed in arbitrary conventional container.
This test kit is used for the treatment of mammalian cancer and comprises:
The ftorafur of (i) treatment effective dose,
(ii) Gimeracil of the amount of antitumous effect is effectively strengthened,
(iii) Oteracil Potassium of the amount of side reaction is effectively suppressed; These are all the parts of anti-tumor compositions, and
(iv) containing effective liposome strengthening the lomustine of the amount of antitumous effect.
This test kit comprises at least 2 containers for these compositions, and ftorafur and lomustine are packaged in point other container.Mentioned component (i) to (iv) preferably in the medicament forms prepared with pharmaceutically acceptable carrier in combination.About mentioned reagent box, as long as composition (i) and (iv) are stored in point other container, composition (ii) and (iii) can independently be stored in the container that the container that stores with above-mentioned two kinds of compositions separates, or composition (ii) and (iii) can mix to be stored in identical container with composition (i) or (iv) independently.Preferred test kit is: containing composition (i) to the medicament storage of (iii) in a container, the medicament storage containing composition (iv) is in another container.
Be used for the treatment of the available units dosage form comprising the antitumor agent mammiferous of the present invention of the mankind suffering from malignant tumor unrestricted, and suitably can select according to therapeutic purposes.Instantiation is the parenteral form such as injection, suppository, collyrium, ointment, aerosol; The oral form such as tablet, coated tablet, powder, granule, capsule, liquid agent, pill, suspension, Emulsion.The antitumor agent of these dosage forms can be produced according to method well known in the art.
Amount as the ftorafur of the active component of anti-tumor agent of the present invention, Gimeracil, Oteracil Potassium and lomustine is different according to dosage form, route of administration, dosage arrangement etc., and unrestricted, therefore can suitably select.Usually preferably the ratio of active component is the weight of about 1% to about 70% of pharmaceutical preparation.
The medication of pharmaceutical preparation of the present invention is unrestricted, and can decide according to the situation of its form, age, sex, patient and other factors; Therefore, can enteral administration, oral administration, rectally, administration in mouth, intraarterial delivery, intravenous administration, percutaneous dosing or administration in a similar fashion.Such as, tablet, pill, solution, suspension, Emulsion, granule, capsule etc. are oral administrations; Injection is intra-arterial or intravenous administration; Suppository is drop rectum with drug; Ointment is applied to skin, oral mucosa etc.About pharmaceutical preparation of the present invention, the medicament that may contain ftorafur, Gimeracil and Oteracil Potassium is oral administration, and is encapsulated in the lomustine medicament intravenous administration in liposome.
In the present invention, the dosage of often kind of active component suitably can be selected according to the degree of application, patient age and sex, disease and other factors.Antitumor effect fortifier of the present invention and anti-tumor agent can administration every day 1-4 agent.
In oral administration, the amount giving pharmaceutical preparation of the present invention preferably uses following scope as standard: the amount of ftorafur is about 0.1-100mg/kg/ days, preferably about 0.2-40mg/kg/ days, more preferably about 0.5-20mg/kg/ days; The amount of Gimeracil is about 0.02-30mg/kg/ days, preferably about 0.05-12mg/kg/ days, more preferably about 0.1-6mg/kg/ days; The amount of Oteracil Potassium is about 0.1-100mg/kg/ days, preferably about 0.2-40mg/kg/ days, more preferably about 0.5-20mg/kg/ days; And the amount of lomustine is about 0.08-200mg/kg/ days, preferably about 0.15-80mg/kg/ days, more preferably about 0.4-40mg/kg/ days.
When pharmaceutical preparation is injection form, progressively adult can be given by it 5 minutes or longer time, common amount is equivalent to the lomustine of the ftorafur of about 0.1-100mg/kg/ days and about 0.08-200mg/kg/ days, this pharmaceutical preparation D/W can be diluted if desired.When pharmaceutical preparation of the present invention is suppository form, by being inserted into rectum every day to adult's administration 1 time or 2 times, interval time 6-12 hour, common amount is equivalent to the lomustine of the ftorafur of about 0.1-100mg/kg/ days and about 0.08-200mg/kg/ days.
Unrestricted by the type of the treatable malignant tumor of the administration of pharmaceutical preparation of the present invention, as long as activity form, namely 5-FU reacts wherein; Such as pulmonary carcinoma, gastric cancer, colon and rectum carcinoma, esophageal carcinoma, breast carcinoma, incidence cancer, hepatocarcinoma, carcinoma of gallbladder/cancer of biliary duct, cancer of pancreas, uterus carcinoma, cervical cancer, ovarian cancer, renal carcinoma, bladder cancer, carcinoma of prostate, pharyngeal cancer, cerebroma, leukemia, melanoma, malignant lymphoma etc.Especially, can expect that pharmaceutical preparation of the present invention has remarkable result to colon cancer, renal carcinoma, gastric cancer, esophageal carcinoma, breast carcinoma and incidence cancer.In addition, also can expect, to typical drug-resistant tumors and the tumor that drug resistance occurring positive, there is remarkable result.
Embodiment
The embodiment hereafter provided and testing example are in order to example the present invention in more detail, but scope of the present invention not by these embodiments and testing example limit.
Embodiment 1
By DPPC (L-α-dipalmitoyl phosphatidyl choline, CoatsomeMC-6060, NOF company manufactures), cholesterol is (superfine, by Wako Pure Chemical Industries, Ltd. (WakoPureChemicalIndustries, Ltd.) manufacture) and mPEG2000-DSPE (1,2-distearyl-sn-glycerol-3-phosphate ethanolamine-n-[methoxyl group (Polyethylene Glycol)-2000], SunbrightDSPE-020CN, NOF company manufactures) be dissolved into the concentration obtaining in chloroform and be respectively 20mM, 50mM and 5mM.Subsequently, the 5mMmPEG2000-DSPE solution of the 20mMDPPC solution of 5ml, the 50mM cholesterol solution of 0.5ml and 1ml is placed in pear shape bottle.While use evaporation under reduced pressure, remove chloroform to form lipid membrane bottom pear shape bottle.Chloroform/the diethyl ether (volume ratio 1:2) of lipid membrane 6ml dissolves.Lomustine is dissolved in the glucose solution of 5% to make the concentration of lomustine become 8mg/ml.The lomustine solution (2ml) prepared thus is joined lipid soln, then mixes.The mixture obtained 25 DEG C ultrasonic 15 minutes to form w/o emulsion, and while vortex oscillation, under using evaporation under reduced pressure, organic facies is removed; Thus lomustine is encapsulated in liposome.Use biofraction instrument (biodisruptor) (Japan Precise Machine Co., Ltd (NipponSeikiCo., Ltd.) supersound process of granule sizing) is carried out, so that the average particulate diameter comprising the liposome of medicament is wherein slightly smaller than 200nm.In order to remove the medicament be not encapsulated in liposome, while by magnetic stirrer, use dialysis cassette (Slide-A-Lyzer dialysis cassette, 10000MWCO, Thermo Fischer Scient Inc. (ThermoScientificInc.) manufacture) and as external solution 5% glucose solution, at 4 DEG C, carry out the dialysis of 2 hours.After changing external solution, carry out another time dialysis of 2 hours while stirring, therefore obtain the Liposomal formulation containing lomustine.Such preparation the average particulate diameter containing the Liposomal formulation of lomustine with 190.2 ± 13.9nm (n=5).
In an embodiment of the present invention, the average particulate diameter of Liposomal formulation is measured by light scattering method by using NICOMP370HPL submicron particles analyser (manufacture of ParticleSizingSystem company).
Embodiment 2
By HSPC (HSPC, CoatsomeNC-21, manufactured by NOF company), cholesterol is (superfine, by Wako Pure Chemical Industries, Ltd. (WakoPureChemicalIndustries, Ltd.) manufacture) and mPEG2000-DSPE (1,2-distearyl-sn-glycerol-3-phosphate ethanolamine-n-[methoxyl group (Polyethylene Glycol)-2000], SunbrightDSPE-020CN, NOF company manufactures) be dissolved into the concentration obtaining in chloroform and be respectively 20mM, 50mM and 5mM.Subsequently, the 5mMmPEG2000-DSPE solution of the 20mMHSPC solution of 5ml, the 50mM cholesterol solution of 1ml and 2ml is placed in pear shape bottle.While use evaporation under reduced pressure, chloroform is removed to form lipid membrane bottom pear shape bottle.Chloroform/the diethyl ether (volume ratio 1:2) of lipid membrane 6ml dissolves.Lomustine is dissolved in the glucose solution of 5% to make the concentration of lomustine become 8mg/ml.The lomustine solution (2ml) prepared thus is joined lipid soln, then mixes.The mixture obtained 35 DEG C ultrasonic 15 minutes to form w/o emulsion, and while vortex oscillation, use evaporimeter under reduced pressure to remove organic making an appointment 1 hour; Thus lomustine is encapsulated in liposome.After this, control particle diameter according to the mode identical with enforcement 1 and remove the medicament do not encapsulated, thus obtaining lomustine liposomes preparation.The Liposomal formulation containing lomustine prepared in this way has the average particulate diameter of 189.9 ± 21.3nm (n=5).
Comparative example 1
By DPPC (L-α-dipalmitoyl phosphatidyl choline, CoatsomeMC-6060, NOF company manufactures), cholesterol is (superfine, by Wako Pure Chemical Industries, Ltd. (WakoPureChemicalIndustries, Ltd.) manufacture) and mPEG2000-DSPE (1,2-distearyl-sn-glycerol-3-phosphate ethanolamine-n-[methoxyl group (Polyethylene Glycol)-2000], SunbrightDSPE-020CN, NOF company manufactures) be dissolved into the concentration obtaining in chloroform and be respectively 20mM, 50mM and 5mM.Subsequently, the 5mMmPEG2000-DSPE solution of the 20mMDPPC solution of 5ml, the 50mM cholesterol solution of 0.5ml and 1ml is placed in pear shape bottle.While use evaporation under reduced pressure, remove chloroform to form lipid membrane bottom pear shape bottle.Chloroform/the diethyl ether (volume ratio 1:2) of lipid membrane 6ml dissolves.L-OHP is dissolved in the glucose solution of 5% to make the concentration of l-OHP become 8mg/ml.The l-OHP solution (2ml) prepared thus is joined lipid soln, then mixes.The mixture obtained 25 DEG C ultrasonic 15 minutes to form w/o emulsion, and while vortex oscillation, under using evaporation under reduced pressure, organic facies is removed; Thus l-OHP is encapsulated in liposome.Use biofraction instrument (biodisruptor) (Japan Precise Machine Co., Ltd (NipponSeikiCo., Ltd.) supersound process of granule sizing) is carried out, so that the average particulate diameter comprising the liposome of medicament is wherein slightly smaller than 200nm.In order to remove the medicament be not encapsulated in liposome, while by magnetic stirrer, use dialysis cassette (Slide-A-Lyzer dialysis cassette, 10000MWCO, Thermo Fischer Scient Inc. (ThermoScientificInc.) manufacture) and as external solution 5% glucose solution, at 4 DEG C, carry out the dialysis of 2 hours.After changing external solution, carry out another time dialysis of 2 hours while stirring, therefore obtain the Liposomal formulation containing l-OHP.Such preparation the average particulate diameter containing the Liposomal formulation of l-OHP with 185.2 ± 14.9nm (n=5).
In an embodiment of the present invention, the average particulate diameter of Liposomal formulation is measured by light scattering method by using NICOMP370HPL submicron particles analyser (manufacture of ParticleSizingSystem company).
Comparative example 2
By HSPC (HSPC, CoatsomeNC-21, manufactured by NOF company), cholesterol is (superfine, by Wako Pure Chemical Industries, Ltd. (WakoPureChemicalIndustries, Ltd.) manufacture) and mPEG2000-DSPE (1,2-distearyl-sn-glycerol-3-phosphate ethanolamine-n-[methoxyl group (Polyethylene Glycol)-2000], SunbrightDSPE-020CN, NOF company manufactures) be dissolved into the concentration obtaining in chloroform and be respectively 20mM, 50mM and 5mM.Subsequently, the 5mMmPEG2000-DSPE solution of the 20mMHSPC solution of 5ml, the 50mM cholesterol solution of 1ml and 2ml is placed in pear shape bottle.While use evaporation under reduced pressure, chloroform is removed to form lipid membrane bottom pear shape bottle.Chloroform/the diethyl ether (volume ratio 1:2) of lipid membrane 6ml dissolves.L-OHP is dissolved in the glucose solution of 5% to make the concentration of l-OHP become 8mg/ml.The l-OHP solution (2ml) prepared thus is joined lipid soln, then mixes.The mixture obtained 35 DEG C ultrasonic 15 minutes to form w/o emulsion, and while vortex oscillation, use evaporimeter under reduced pressure to remove organic making an appointment 1 hour; Thus l-OHP is encapsulated in liposome.After this, control particle diameter according to the mode identical with enforcement 1 and remove the medicament do not encapsulated, thus obtaining l-OHP Liposomal formulation.The Liposomal formulation containing l-OHP prepared in this way has the average particulate diameter of 197.9 ± 22.0nm (n=5).
Test case 1
Use the Liposomal formulation (being hereafter called DPPC liposome lomustine) containing lomustine obtained in embodiment 1.
By the contents melting be encapsulated in TS-1 capsule has been prepared TS-1 preparation (being hereafter called TS-1) in water.
At 5%CO
2, at 37 DEG C, by metastatic for height lung carcinoma cell, namely Lewis lung cancer (LLC) is cultivated in the DMEM of 10% hyclone.Containing 5 × 10
6the 0.1ml LLC cell subcutaneous injection of individual cell/mL to the back of male C57BL/6 mice (in 5 week age, body weight is 20g), to obtain the mice of carrying solid tumor.Verified, apart from LLC cell infusion 6 days, the gross tumor volume gone out according to formulae discovery was below more than 50mm
3.
DPPC liposome lomustine or DPPC liposome l-OHP intravenous administration, dosage is 4.2mg/kg according to lomustine or l-OHP.TS-1 oral administration, dosage is 6.9mg/kg according to ftorafur.DPPC liposome lomustine or DPPC liposome l-OHP are in postvaccinal 13rd day of cell and administration in the 20th day, and TS-1 is from latter 6 days of cell inoculation until experiment terminates administration every day.
From latter 6 days of cell inoculation, gross tumor volume was according to formulae discovery below.Use relative tumour volume ratio as metrics evaluation antitumor action.
Gross tumor volume=1/2 × a × b
2
(a: the major axis of knub position, b: the minor axis of knub position)
See from result shown in Fig. 1 is clear, DPPC liposome lomustine demonstrates better antitumous effect with the conjoint therapy of TS-1 than the conjoint therapy of DPPC liposome l-OHP and TS-1.
Test case 2
Antitumous effect is evaluated, except employing the Liposomal formulation (being hereafter called HSPC liposome lomustine) containing lomustine obtained in embodiment 2 in the mode identical with testing example 1.
See from the result shown in Fig. 2 is clear, HSPC liposome lomustine demonstrates better antitumous effect with the conjoint therapy of TS-1 than combining of HSPC liposome l-OHP and TS-1.
Applicant states, the present invention illustrates detailed features of the present invention and method detailed by above-described embodiment, but the present invention is not limited to above-mentioned detailed features and method detailed, namely do not mean that the present invention must rely on above-mentioned detailed features and method detailed could be implemented.Person of ordinary skill in the field should understand, any improvement in the present invention, to equivalence replacement and the interpolation of auxiliary element, concrete way choice etc. that the present invention selects component, all drops within protection scope of the present invention and open scope.
Claims (10)
1. an antitumor effect fortifier, it is the Liposomal formulation of the lomustine containing effective dose, and it is for improving the anti-tumor activity of the combination medicine of the treatment effective dose containing ftorafur, Gimeracil and Oteracil Potassium.
2. antitumor effect fortifier according to claim 1, is characterized in that, in the lipid components of described Liposomal formulation, at least one is phospholipid;
Preferably, the film surface Polyethylene Glycol of described liposome, polyglycerine or cation lipid are modified.
3. antitumor effect fortifier according to claim 1 and 2, is characterized in that, the molar ratio of described lomustine and ftorafur is 0.5-2:1.
4. the antitumor effect fortifier according to any one of claim 1-3, it is characterized in that, in the combination medicine of the described treatment effective dose containing ftorafur, Gimeracil and Oteracil Potassium, the Gimeracil used and the molar ratio of ftorafur are 0.5-2:1, and the molar ratio of the Oteracil Potassium used and ftorafur is 0.5-2:1.
5. an antitumor agent, it comprises the combination of Liposomal formulation and combination medicine, and described Liposomal formulation obtains by being encapsulated in liposome by lomustine, and described combination medicine contains ftorafur, Gimeracil and Oteracil Potassium.
6. antitumor agent according to claim 5, is characterized in that, in the lipid components of described Liposomal formulation, at least one is phospholipid;
Preferably, the film surface Polyethylene Glycol of described liposome, polyglycerine or cation lipid are modified.
7. the antitumor agent according to claim 5 or 6, is characterized in that, the molar ratio of described lomustine and ftorafur is 0.5-2:1.
8. the antitumor agent according to any one of claim 5-7, it is characterized in that, in the combination medicine of the described treatment effective dose containing ftorafur, Gimeracil and Oteracil Potassium, the Gimeracil used and the molar ratio of ftorafur are 0.5-2:1, and the molar ratio of the Oteracil Potassium used and ftorafur is 0.5-2:1.
9. the antitumor agent according to any one of claim 5-8, it is characterized in that, described antitumor agent consists of test kit, and described test kit comprises Liposomal formulation and combination medicine, described Liposomal formulation contains lomustine, and described combination medicine contains ftorafur, Gimeracil and Oteracil Potassium.
10. the antitumor agent according to any one of claim 5-9, is characterized in that, described Liposomal formulation is by intravenous, intraperitoneal, intramuscular or subcutaneous administration, and the combination medicine oral administration containing ftorafur, Gimeracil and Oteracil Potassium.
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| CN1839811A (en) * | 2006-01-19 | 2006-10-04 | 浙江大学 | Lomustine liposome freeze-drying powder injection and its preparation method |
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| CN106619689A (en) * | 2016-12-30 | 2017-05-10 | 陈晓华 | Medicine composition and kit for therapy of cancer and application thereof |
| CN106619689B (en) * | 2016-12-30 | 2018-05-01 | 陈晓华 | It is a kind of for the pharmaceutical composition for the treatment of cancer, kit and its application |
| WO2018121669A1 (en) * | 2016-12-30 | 2018-07-05 | 陈晓华 | Pharmaceutical composition for treating cancer and use thereof |
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