CN101461784A - Method for preparing nano magnetic microballoons and anticancer oral preparation prepared using the method - Google Patents
Method for preparing nano magnetic microballoons and anticancer oral preparation prepared using the method Download PDFInfo
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Abstract
The invention discloses a method for preparing nanometer magnetic microspheres and an anticancer oral preparation prepared by utilizing the method. The method comprises the process steps of: a, material preparation, in which a carrier material, a framework material, a drug and a solvent are prepared; b, the preparation; c, the stability and drying; and d, the crushing and preparation and so on. The method takes beta-cyclodextrin as the framework material and includes the carrier material (a nanometer magnetic biomaterial) and drug combination and so on. The drug-loaded nanometer magnetic microspheres can quickly reach appointed focus target positions, penetrate target cell membranes to enter cells, realize the trans-membrane transport of target macromolecules, achieve the effects of targeted release and slow/controlled release, improve the drug concentration in target cells, and inhibit the gene expression and amplification of the target cells to ensure that the target cells are degenerated to necrotize or apoptosize; at the same time, the microspheres strengthen the killing activity of T cells and NK cells and the phagotrophic ability of macrophages to the target cells, improve the immunity of organisms, and achieve the effects of multiple treatment and multi-drug resistance reverse.
Description
Technical field
The present invention relates to a kind of preparation method of novel tumor medicine, the preparation method of particularly novel medicament-carried nano magnetic microsphere, and the application in the tumour medicine oral formulations.
Background technology
About " nano-magnetic biomaterial " application in biomedicine field, disclosed at present technology mainly contains: applied research, super paramagnetic iron oxide nanoparticle extensive clinical practice and the nano-magnetic biomaterial preparation capable of permeating skin technology in magnetic resonance imaging contrast of various drug loaded magnetic nanoparticle/microcapsules/microsphere in injection is applied in the department of dermatologry medicine for external use OTC series of products (comprising liquid, powder, ointment etc.).
" medicament-carried nano magnetic microsphere " (also claiming " medicament-carried nano magnetic microcapsule ", " nano-magnetic biological missile "), have favorable biological degradability and biocompatibility, can effectively promote drug absorption, improve drug bioavailability, its good targeting and slow controlled release effect are the important assurances that improves curative effect of medication, reduces toxic and side effects.
The super paramagnetic Fe of " nano-magnetic biomaterial "-nanoscale
3O
4, be disclosed mature technology, have very definite safety, be widely used in biomedicine field.Because this carrier has very unique physicochemical property, especially be suitable as " guided missile head " of the oral targeting preparation of the present invention.
The magnetic resonance imaging contrast clinical research confirmation: Superparamagnetic Iron Oxide has magnetic torque, volume is little, have biological degradability and biocompatibility, its toxicity threshold reaches more than the 15g for the total amount of ferrum in the normal human, or iron content reaches more than the 200 μ g in every gram hepatic tissue, and the actual amount of Superparamagnetic Iron Oxide is all much smaller than its toxicity threshold in the clinical practice at present.
The present various Chinese herbal medicine oral formulations of the various common cancers of being used for the treatment of of preparing of the marketization and disclosed technology or auxiliary treatment, ubiquity has following shortcoming: 1, the effective ingredient of medicine can not arrive the specified focus target position of human body fast, drug release suffers that reticuloendothelial system (RES) is to its non-selective removing, have influence on the normal healthy histiocyte in the process that medicine is digested and assimilated in human body simultaneously, especially the side effect that liver,spleen,kidney etc. is produced is very big.2, medicine suffers the metabolism and the degraded of enzyme system in the violent environment of digestive tract, and medicine macromole (effective ingredient) is difficult to permeates cell membranes and enters in the cell and fully absorbed simultaneously, and bioavailability of medicament is very low.
Summary of the invention
At the deficiency that prior art exists, first purpose of the present invention is: provide a kind of framework material with special physicochemical property, enclose carrier material and antitumor drug combination, the preparation method of preparation medicament-carried nano magnetic microsphere.
Second purpose of the present invention is: this medicament-carried nano magnetic microsphere new technique is applied in the antineoplastic agent composition oral preparation, this medicament-carried nano magnetic microsphere can arrive the specified focus target position of human body fast, enter target cell, the targeting of realizing medicine discharges and slowly releasing effect, improve the drug level in the target cell, and do not have influence on the normal healthy histiocyte, human body immunity improving power, activate patient's vivo antitumor mechanism, reduce the canceration probability, induce and promote apoptosis of tumor cells, reach multiple treatment and multi-medicine tolerant reversal effect.
The present invention solves the technical scheme that its technical problem takes: a kind of nano-magnetic microsphere preparation method, comprise the steps: a, get the raw materials ready: prepare carrier material, framework material, medicine and solvent, wherein, carrier material is the nano-magnetic biomaterial, is the Fe of particle diameter between 2～20nm
3O
4Powder body, framework material are beta-schardinger dextrin-, Fe
3O
4The weight ratio of powder body and beta-schardinger dextrin-and medicine is: 0.001～0.01:1:1, and solvent is an amount of; B, preparation: beta-schardinger dextrin-and medicine are added in the variable-ratio food blending machine, stirred 5 to 15 minutes, add Fe then with 50～200 rev/mins frequency average rates
3O
4Behind the powder body again average rate stirred 30～90 minutes, change with 50～500 rev/mins of frequencies and stir, and the slow continuously solvent that injects, take out to the pulping and pour supermolecule envelope chemical combination machine into, start envelope chemical combination head and take out and pour into container after 30～120 minutes with 1000～3000 rev/mins frequency envelope chemical combination; C, stable and dry: after treating that slurry is stablized 24 hours, carry out 40～65 ℃ of freeze-day with constant temperature, target humidity is 5～12%; D, pulverizing and preparation: the medicine that drying is good sieves fill capsule or compress tablet coating after pulverizing and reaching 80～325 orders.
Described nano-magnetic microsphere preparation method, described medicine are hydrophilic medicament or drug regimen, and solvent for use is the water of Ph value 6～7, and the weight ratio of medicine and solvent is 1:1～2.
Described nano-magnetic microsphere preparation method, described medicine are hydrophobic alcohol soluble drug or drug regimen, and solvent for use is 50～95% ethanol, and the weight ratio of medicine and solvent is 1:1～2.
Described nano-magnetic microsphere preparation method, described medicine are oil phase and fat-soluble medicine or drug regimen, and solvent for use is the water of Ph value 6～7, and the weight ratio of medicine and solvent is 1:2～3.
Described nano-magnetic microsphere preparation method, described medicine are modern Chinese medicine compound recipe, natural drug compound recipe or chemicals compound recipe.
The Orally applied anticancer agent of described nano-magnetic microsphere preparation method preparation, the used medicine of described Orally applied anticancer agent is the modern Chinese medicine compound recipe, and the weight quota of every kind of medicine water extract powder is respectively in the prescription: 30 parts of Herba Scutellariae Barbataes, 15 parts of Herba Violaes, 10 parts of Pseudobulbus cremastrae seu pleiones, 10 parts of Rhizoma Polygoni Cuspidati, 10 parts of Spora Lygodii, 10 parts of the Radixs Astragali, 5 parts of Herba Poae Sphondylodiss, 5 parts of Radix Curcumaes, 4 parts of Rhizoma Chuanxiongs, 1 part of Venenum Bufonis.
The Orally applied anticancer agent of described nano-magnetic microsphere preparation method preparation, the used medicine of described Orally applied anticancer agent is the natural drug compound recipe, this prescription is made up of modern Chinese medicine and chemicals, described modern Chinese medicine accounts for the 80-98% of whole medicament composing prescription, described chemicals accounts for the 20-2% of whole medicament composing prescription, and the weight quota of the alcohol extract powder of the every kind of medicine of modern Chinese medicine compound recipe in the prescription is respectively: 30 parts of Herba Scutellariae Barbataes, 15 parts of Herba Violaes, 10 parts of Pseudobulbus cremastrae seu pleiones, 10 parts of Rhizoma Polygoni Cuspidati, 10 parts of Spora Lygodii, 10 parts of the Radixs Astragali, 5 parts of Herba Poae Sphondylodiss, 5 parts of Radix Curcumaes, 4 parts of Rhizoma Chuanxiongs, 1 part of Venenum Bufonis; The weight quota of the every kind of medicine of chemicals compound recipe in the prescription is respectively 80 parts of ifosfamides, 20 parts of paclitaxels.
The Orally applied anticancer agent of described nano-magnetic microsphere preparation method preparation, the used medicine of described Orally applied anticancer agent is the chemicals compound recipe, the weight quota of every kind of medicine is respectively in the compound recipe: 50 parts of 5-flurouracil, 40 parts of ifosfamides, 1 part of 9 parts of paclitaxels and doxorubicin hydrochloride.
Medicament-carried nano magnetic microsphere of the present invention has favorable biological degradability and biocompatibility, can effectively promote drug absorption, improve drug bioavailability, its good targeting and slow controlled release effect are the important assurances that improves curative effect of medication, reduces toxic and side effects.The medicament-carried nano magnetic microsphere can be by specificity passage (OprD)-" the film ion channel " or the non-specific passage (OprF) of epicyte, bring into ingredient and bioactie agent in the target cell smoothly, suppress gene expression and the amplification of target cell, change its some biochemical character and apoptosis and suppress, make its degeneration necrosis or apoptosis.Because there is multiple resistance mechanism in the persister cell, drug molecule is big more, and institute is electronegative many more, and hydrophobicity is strong more, and the difficult more non-specific passage (OprF) by epicyte can not form active drug concentration in the cell, so that produces drug resistance.After if the macromole of medicine is granulated into the micromolecule of nanometer particle size level, just can the penetrate tissue gap, and can be by the blood capillary of human body minimum.The medicament-carried nano magnetic microsphere improves the drug level in the target cell because the dimensional effect and the skin effect of self uniqueness can enter target cell smoothly, reaches the multi-medicine tolerant reversal effect." multi-medicine tolerant reversal " can make the probability of oncotherapy failure descend, and has very high clinical value.
The oral delivery strategy of most macromolecular drugs is basic identical, allows macromolecular drug in the system avoid the degraded of enzyme exactly, improves the see through efficient of medicine at the gastrointestinal epithelial cells film simultaneously.Medicament-carried nano magnetic microsphere delivery system just in time satisfies this 2 requirements, and the macromolecular drug that they can protect easy inactivation is avoided the metabolism and the degraded of enzyme system in the violent environment of digestive tract.Under the situation that does not add penetrating agent, these particulate carriers can be absorbed by gastrointestinal epithelial cells, realize the macromolecular transmembrane transport of target, overcome biological barrier maximum in this macromole oral administration route.
The proteic receptor TfR of iron transfer is all arranged on the film of any growth, proliferative cell.Carry Fe
3+Iron transfer albumen (transferrin; Tf) with receptors bind after endocytosis enter in the cell, for synthetic utilization the in the cell.Especially tumor cell, the expression density of TfR, and obviously increase with the Tf affinity than much higher times of most normal cells at tumor cell; TfR is stable at tumor cell surface expression, is seldom modified, covers or lose; Receptor is an endocytosis, enters Cytoplasm easily, many tumors such as hepatocarcinoma, breast carcinoma and cancer of pancreas etc., all high expressed TfR (TfR).Known that cancerous cell needs a large amount of iron ions to come repetition DNA, so the iron concentration in the cancerous cell is than Normocellular concentration height.The cancerous cell surface exists than the more ferrum biography of normal cell protein receptor.Because cancerous cell makes the medicament-carried nano magnetic microsphere have very high targeting to the greediness of ferrum.
Orally applied anticancer agent of the present invention is to be the anticarcinogen oral formulations of primary raw material preparation with medicament-carried nano magnetic microsphere and Chinese medicine cancer-resisting substance, it carries nano meter biomaterial, bioactive materials, Chinese medicine cancer-resisting substance etc. by the nano-magnetic biological missile, arrive rapidly and specify the focus target position, enter target cell, the targeting of realizing medicine discharges and slowly releasing effect, suppress gene expression and the amplification of target cell, change its some biochemical character and apoptosis and suppress, make its degeneration necrosis or apoptosis; Strengthen the killing activity of NK cell T cell and the macrophage phagocytic activity to target cell simultaneously, human body immunity improving power reaches multiple treatment and multi-medicine tolerant reversal effect.Its medicament-carried nano magnetic microsphere can arrive the specified focus target position of human body fast, and does not have influence on the normal healthy histiocyte; Simultaneously can make the effective ingredient permeates cell membranes of medicine enter target cell smoothly, realize the macromolecular transmembrane transport of target, overcome biological barrier maximum in this macromole oral administration route, improve the drug level in the target cell, anti-cancer and inhibiting tumor, removing toxic substances and promoting subsidence of swelling, removing blood stasis and activating blood flow, removing obstruction in the collateral to relieve pain, be applicable to breast carcinoma, cervical cancer, hepatocarcinoma, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, rectal cancer etc., can effectively suppress tumour cell division propagation, human body immunity improving power, activate patient's vivo antitumor mechanism, reduce the canceration probability, induce and promote apoptosis of tumor cells, reach multiple treatment and multi-medicine tolerant reversal effect.
The specific embodiment
Embodiment one
Make a kind of novel nano magnetic microsphere, comprise the steps:
A, get the raw materials ready: prepare carrier material, framework material, medicine and solvent, wherein, carrier material is the nano-magnetic biomaterial, i.e. the Fe of particle diameter between 2～20nm
3O
4Powder body, framework material are beta-schardinger dextrin-, and medicine is hydrophilic modern Chinese medicine compound recipe, and solvent for use is the water of Ph value 6～7.The weight ratio of carrier material, framework material, medicine and solvent is: 0.001～0.01:1:1:1～2.
B, preparation: beta-schardinger dextrin-and medicine are added in the variable-ratio food blending machine, stirred 5 to 15 minutes, add Fe then with 50～200 rev/mins frequency average rates
3O
4Behind the powder body again average rate stirred 30～90 minutes, change with 50～500 rev/mins of frequencies and stir, and the slow continuously water that injects, take out to the pulping and pour supermolecule envelope chemical combination machine into, start envelope chemical combination head and take out and pour into container after 30～120 minutes with 1000～3000 rev/mins frequency envelope chemical combination;
C, stable and dry: treat that slurry stablizes that to carry out 40～65 ℃ of freeze-day with constant temperature after 24 hours be 5～12% to humidity;
D, pulverizing and preparation: the medicine that drying is good sieves fill capsule or compress tablet coating after pulverizing and reaching 80～325 orders.
Embodiment two
Make a kind of novel nano magnetic microsphere, comprise the steps:
A, get the raw materials ready: prepare carrier material, framework material, medicine and solvent, wherein, carrier material is the nano-magnetic biomaterial, i.e. the Fe of particle diameter between 2～20nm
3O
4Powder body, framework material are beta-schardinger dextrin-, and medicine is the natural drug compound recipe of hydrophobic alcohol dissolubility, and solvent for use is 50～95% ethanol.The weight ratio of carrier material, framework material, medicine and solvent is: 0.001～0.01:1:1:1～2.
B, preparation: beta-schardinger dextrin-and medicine are added in the variable-ratio food blending machine, stirred 5 to 15 minutes, add Fe then with 50～200 rev/mins frequency average rates
3O
4Behind the powder body again average rate stirred 30～90 minutes, change with 50～500 rev/mins of frequencies and stir, and slow continuously 50～95% the ethanol that injects, take out to the pulping and pour supermolecule envelope chemical combination machine into, start envelope chemical combination head and take out and pour into container after 30～120 minutes with 1000～3000 rev/mins frequency envelope chemical combination;
C, stable and dry: treat that slurry stablizes that to carry out 40～65 ℃ of freeze-day with constant temperature after 24 hours be 5～12% to humidity;
D, pulverizing and preparation: the medicine that drying is good sieves fill capsule or compress tablet coating after pulverizing and reaching 80～325 orders.
Embodiment three
Make a kind of novel nano magnetic microsphere, comprise the steps:
A, get the raw materials ready: prepare carrier material, framework material, medicine and solvent, wherein, carrier material is the nano-magnetic biomaterial, i.e. the Fe of particle diameter between 2～20nm
3O
4Powder body, framework material are beta-schardinger dextrin-, and medicine is oil phase and fat-soluble medicine or drug regimen, and solvent is the water of Ph value 6～7.The weight ratio of carrier material, framework material, medicine and solvent is: 0.001～0.01:1:1:2～3.
B, preparation: beta-schardinger dextrin-and medicine are added in the variable-ratio food blending machine, stirred 5 to 15 minutes, add Fe then with 50～200 rev/mins frequency average rates
3O
4Behind the powder body again average rate stirred 30～90 minutes, change with 50～500 rev/mins of frequencies and stir, and the slow continuously water that injects, take out to the pulping and pour supermolecule envelope chemical combination machine into, start envelope chemical combination head and take out and pour into container after 30～120 minutes with 1000～3000 rev/mins frequency envelope chemical combination;
C, stable and dry: treat that slurry stablizes that to carry out 40～65 ℃ of freeze-day with constant temperature after 24 hours be 5～12% to humidity;
D, pulverizing and preparation: the medicine that drying is good sieves fill capsule or compress tablet coating after pulverizing and reaching 80～325 orders.
Utilize above-mentioned three kinds of dissimilar nano-magnetic microspheres, prepare the oral formulations of three kinds of different anticarcinogen prescriptions respectively, the specific embodiment:
Embodiment one
Prepare a kind of new antitumor drug oral formulations, comprise the steps:
A, get the raw materials ready: prepare carrier material, framework material, medicine and solvent, wherein, carrier material is the nano-magnetic biomaterial, i.e. the Fe of particle diameter between 2～20nm
3O
4Powder body, framework material is a beta-schardinger dextrin-, medicine is hydrophilic modern Chinese medicine compound recipe, the weight quota of the water extract powder of every kind of medicine is respectively: 30 parts of Herba Scutellariae Barbataes, 15 parts of Herba Violaes, 10 parts of Pseudobulbus cremastrae seu pleiones, 10 parts of Rhizoma Polygoni Cuspidati, 10 parts of Spora Lygodii, 10 parts of the Radixs Astragali, 5 parts of Herba Poae Sphondylodiss, 5 parts of Radix Curcumaes, 4 parts of Rhizoma Chuanxiongs, 1 part of Venenum Bufonis, solvent for use is the water of Ph value 6～7, and the weight ratio of carrier material, framework material, medicine and solvent is: 0.001～0.01:1:1:1～2.
B, preparation: beta-schardinger dextrin-and medicine are added in the variable-ratio food blending machine, stirred 5 to 15 minutes, add Fe then with 50～200 rev/mins frequency average rates
3O
4Behind the powder body again average rate stirred 30～90 minutes, change with 50～500 rev/mins of frequencies and stir, and the slow continuously water that injects, take out to the pulping and pour supermolecule envelope chemical combination machine into, start envelope chemical combination head and take out and pour into container after 30～120 minutes with 1000～3000 rev/mins frequency envelope chemical combination;
C, stable and dry: treat that slurry stablizes that to carry out 40～65 ℃ of freeze-day with constant temperature after 24 hours be 5～12% to humidity;
D, pulverizing and preparation: the medicine that drying is good sieves fill capsule or compress tablet coating after pulverizing and reaching 80～325 orders.
Embodiment two
Prepare a kind of new antitumor drug oral formulations, comprise the steps:
A, get the raw materials ready: prepare carrier material, framework material, medicine and solvent, wherein, carrier material is the nano-magnetic biomaterial, is the Fe of particle diameter between 2～20nm
3O
4Powder body, framework material is a beta-schardinger dextrin-, medicine is the natural drug compound recipe of hydrophobic alcohol dissolubility, form by modern Chinese medicine prescription and chemicals prescription, described modern Chinese medicine prescription accounts for the 80-98% of whole medicaments compound, described chemicals prescription accounts for the 20-2% of whole medicaments compound, and wherein the weight quota of the alcohol extract powder of every kind of medicine of modern Chinese medicine prescription is respectively: 30 parts of Herba Scutellariae Barbataes, 15 parts of Herba Violaes, 10 parts of Pseudobulbus cremastrae seu pleiones, 10 parts of Rhizoma Polygoni Cuspidati, 10 parts of Spora Lygodii, 10 parts of the Radixs Astragali, 5 parts of Herba Poae Sphondylodiss, 5 parts of Radix Curcumaes, 4 parts of Rhizoma Chuanxiongs, 1 part of Venenum Bufonis; Wherein the weight quota of every kind of medicine of chemicals prescription is respectively 80 parts of ifosfamides, 20 parts of paclitaxels.Solvent for use is 50～95% ethanol.The weight ratio of carrier material, framework material, medicine and solvent is: 0.001～0.01:1:1:1～2.
B, preparation: beta-schardinger dextrin-and medicine are added in the variable-ratio food blending machine, stirred 5 to 15 minutes, add Fe then with 50～200 rev/mins frequency average rates
3O
4Behind the powder body again average rate stirred 30～90 minutes, change with 50～500 rev/mins of frequencies and stir, and slow continuously 50～95% the ethanol that injects, take out to the pulping and pour supermolecule envelope chemical combination machine into, start envelope chemical combination head and take out and pour into container after 30～120 minutes with 1000～3000 rev/mins frequency envelope chemical combination;
C, stable and dry: treat that slurry stablizes that to carry out 40～65 ℃ of freeze-day with constant temperature after 24 hours be 5～12% to humidity;
D, pulverizing and preparation: the medicine that drying is good sieves fill capsule or compress tablet coating after pulverizing and reaching 80～325 orders.
Embodiment three
Prepare a kind of new antitumor drug oral formulations, comprise the steps:
A, get the raw materials ready: prepare carrier material, framework material, medicine and solvent, wherein, carrier material is the nano-magnetic biomaterial, i.e. the Fe of particle diameter between 2～20nm
3O
4Powder body, framework material are beta-schardinger dextrin-, and medicine is oil phase and fat-soluble medicine or drug regimen, solvent is the water of Ph value 6～7, and medicine is the chemicals compound recipe, and the weight quota of every kind of medicine is respectively: 50 parts of 5-flurouracil, 40 parts of ifosfamides, 1 part of 9 parts of paclitaxels and doxorubicin hydrochloride.The weight ratio of carrier material, framework material, medicine and solvent is: 0.001～0.01:1:1:2～3
B, preparation: beta-schardinger dextrin-and medicine are added in the variable-ratio food blending machine, stirred 5 to 15 minutes, add Fe then with 50～200 rev/mins frequency average rates
3O
4Behind the powder body again average rate stirred 30～90 minutes, change with 50～500 rev/mins of frequencies and stir, and the slow continuously water that injects, take out to the pulping and pour supermolecule envelope chemical combination machine into, start envelope chemical combination head and take out and pour into container after 30～120 minutes with 1000～3000 rev/mins frequency envelope chemical combination;
C, stable and dry: treat that slurry stablizes that to carry out 40～65 ℃ of freeze-day with constant temperature after 24 hours be 5～12% to humidity;
D, pulverizing and preparation: the medicine that drying is good sieves fill capsule or compress tablet coating after pulverizing and reaching 80～325 orders.
Illustrate: the various descriptions of plant equipment of the present invention, carrier material, framework material, drug regimen and solvent etc. all belong to domestic commercially available prod/commodity.
To the Orally applied anticancer agent of the present invention's preparation, special commission's TOEFL is built provincial institute for drug control and is tested, and its concrete survey report is as follows:
Experiment material
1.1 animal: cleaning level ICR mice
1.2 be subjected to the reagent thing: the Orally applied anticancer agent of the present invention's preparation, specification is the 0.25g/ grain, people's oral dose is 0.1g/kg.The content of medicine of the present invention is configured to for the test liquid that tries concentration with the distilled water agitation grinding before this; Before facing, Cyclophosphamide for injection disposes 1.75mg/ml concentration with distilled water.
1.3 tumor strain: cervical cancer U
14Ascitic type liver cancer H
22
2. experimental technique and result
2.1 acute toxicity testing:
Can't measure LD
50Situation under, get 20 of body weight 18-21g mices, male and female half and half, fasting 16H before the experiment can't help water, give the mouse stomach administration with maximum administration concentration 0.44g/ml, maximum administration volume 0.04ml/gBW, the upper and lower noon each 1 time, normally raise after the administration, observed continuously 14 days, mice no abnormality seen, all survival.It is 35.3g/kg to mouse stomach administration maximum tolerated dose that the result records medicine of the present invention, is equivalent to 352 times of the clinical consumption of people.
2.2 anti-solid type transplantability malignant tumor cervical cancer U
14Experiment:
Get 50 of body weight 18-22g female mices, under aseptic condition, produce on the good cervical cancer mice from inoculating 10 days tumors, choose intact tumor piece, reject peplos and downright bad part, be cut into small pieces, adding normal saline by 1:6 places in the glass homogenizer and grinds, filter, be mixed with tumor cell suspension, it is subcutaneous to be seeded in every right side of mice forelimb axillary fossa respectively by 0.01ml/gBW, behind the inoculation 24h mice is divided into 5 groups at random by body weight, every group 10, the administration group is respectively with 30,65, the medicine of the present invention of 125mg/ml concentration, administration volume 0.02ml/gBW gastric infusion, every day 1 time, 24h weighs after the drug withdrawal again, puts to death mice, strips out tumor and weighs.The blank group awards the equal-volume distilled water, and positive controls is irritated stomach in inoculation back 24h and awarded cyclophosphamide 35mg/kg1 time.Introduce tumor control rate by following formula, experimental data is carried out one factor analysis of variance with spss10.0 software, and through the variance analysis check, the neat experimental data of variance adopts the Isd method to carry out statistical analysis, the experimental data of heterogeneity of variance adopts the tambane method to carry out statistical analysis, the results are shown in Table 1,2
Table 1 medicine of the present invention is irritated stomach to mouse cervical cancer U
14The inhibitory action of growth (X ± S, n=10)
Compare with the blank group,
*P＜0.05,
*: p＜0.01
Table 2 medicine of the present invention is irritated stomach to cervical cancer U
14The influence of mice body weight (g, X ± S)
The filling stomach 1.3 of result's medicine of the present invention, 2.5g/kg dosage group are to inoculation cervical cancer U
14The tumour inhibiting rate of mice is respectively 92.2%, 99.3%, analyzes (F check) and the equal significance of blank group comparing difference (P＜0.05, P＜0.01) by statistics, illustrates that the present invention is to solid type tumor cervical cancer U
14Mice has tangible tumor-inhibiting action, and CPM group shows positive effect, and tumour inhibiting rate is 83.3 (P＜0.05), and respectively organizes the mice body weight and all do not alleviate (P〉0.05).
2.3 anti-ascitic type inhibition malignant tumor hepatocarcinoma (H
22) experiment:
Get 55 of body weight 22-26g female mices, under aseptic condition, from inoculating 7 days well-grown ascitic type (H
22) mouse peritoneal gets ascites and make 1:8 tumor cell normal saline suspension, give every mouse peritoneal inoculation 0.01ml/gBW respectively, behind the inoculation 24h my body weight of mice is divided into 5 groups at random, every group 11, the administration group respectively with 125,250, the health of 500mg/ml concentration likes capsule test liquid, administration volume 0.02ml/gBW gastric infusion, every day 1 time, continuous 7 days, the blank group gave the equal-volume distilled water, and positive controls is irritated stomach every other day for 1 time and given cyclophosphamide (CPM) 35mg/kg totally 4 times.The dead mouse situation respectively organized in record, to the 30th day, be calculated as follows life and prolong percentage rate, experimental data is carried out one factor analysis of variance with SPSSI0.0 software, through the variance test of homogeneity, the neat experimental data of variance adopts LSD to carry out statistical analysis, and the experimental data of heterogeneity of variance adopts Tamhane to carry out statistical analysis, the results are shown in Table 3.
Table 3 medicine of the present invention is irritated stomach to mouse hydroperitoneum type hepatocarcinoma (H
22) life prolongation effect influence (X ± S, n=11)
★: 3 mice existence death in 30 days is arranged in this group.One: reduce % than distilled water group life.
Result's medicine of the present invention is irritated stomach 2.5,10.0g/kg dosage group to ascitic type liver cancer (H
22) increase in life span of mice is respectively 30.7,34.6%, analyze (F check) and the equal nonsignificance of blank group comparing difference (P〉0.5) by statistics, and health likes that capsule 10.0g/kg group has 3 mice survivals (healing) above 30 days, illustrates that medicine of the present invention has prolongation ascitic type liver cancer (H
22) trend of mice life, but DeGrain.
3. brief summary
Medicine of the present invention is lower to mouse stomach administration toxicity, and MTD is 35.2g/kg, is equivalent to 352 times of the clinical consumption of people; To solid type tumor cervical cancer (U
14) mouse stomach administration tumour inhibiting rate reaches 92.2% respectively (P〉0.05), 99.3% (P〉0.01), show that solid tumor is had tangible tumor-inhibiting action.To ascitic type tumor hepatocarcinoma (H
22) increase in life span of mouse stomach administration is respectively 30.7%, 34.6%, and prolongation ascitic type liver cancer (H is arranged
22) trend of mice life, but with blank group comparing difference nonsignificance (P〉0.5), show ascitic type liver cancer (H
22) drug effect is not obvious.
Claims (8)
1, a kind of nano-magnetic microsphere preparation method is characterized in that: comprise the steps: a, get the raw materials ready: prepare carrier material, framework material, medicine and solvent, wherein, carrier material is the nano-magnetic biomaterial, is the Fe of particle diameter between 2～20nm
3O
4Powder body, framework material are beta-schardinger dextrin-, Fe
3O
4The weight ratio of powder body and beta-schardinger dextrin-and medicine is: 0.001～0.01:1:1, and solvent is an amount of; B, preparation: beta-schardinger dextrin-and medicine are added in the variable-ratio food blending machine, stirred 5 to 15 minutes, add Fe then with 50～200 rev/mins frequency average rates
3O
4Behind the powder body again average rate stirred 30～90 minutes, change with 50～500 rev/mins of frequencies and stir, and the slow continuously solvent that injects, take out to the pulping and pour supermolecule envelope chemical combination machine into, start envelope chemical combination head and take out and pour into container after 30～120 minutes with 1000～3000 rev/mins frequency envelope chemical combination; C, stable and dry: after treating that slurry is stablized 24 hours, carry out 40～65 ℃ of freeze-day with constant temperature, target humidity is 5～12%; D, pulverizing and preparation: the medicine that drying is good sieves fill capsule or compress tablet coating after pulverizing and reaching 80～325 orders.
2, nano-magnetic microsphere preparation method according to claim 1 is characterized in that: described medicine is hydrophilic medicament or drug regimen, and solvent for use is the water of Ph value 6～7, and the weight ratio of medicine and solvent is 1:1～2.
3, nano-magnetic microsphere preparation method according to claim 1 is characterized in that: described medicine is hydrophobic alcohol soluble drug or drug regimen, and solvent for use is 50～95% ethanol, and the weight ratio of medicine and solvent is 1:1～2.
4, nano-magnetic microsphere preparation method according to claim 1 is characterized in that: described medicine is oil phase and fat-soluble medicine or drug regimen, and solvent for use is the water of Ph value 6～7, and the weight ratio of medicine and solvent is 1:2～3.
5, nano-magnetic microsphere preparation method according to claim 1 is characterized in that: described medicine is modern Chinese medicine compound recipe, natural drug compound recipe or chemicals compound recipe.
6, utilize the Orally applied anticancer agent of the described nano-magnetic microsphere preparation method preparation of claim 1, it is characterized in that: the used medicine of described Orally applied anticancer agent is the modern Chinese medicine compound recipe, and the weight quota of every kind of medicine water extract powder is respectively in the prescription: 30 parts of Herba Scutellariae Barbataes, 15 parts of Herba Violaes, 10 parts of Pseudobulbus cremastrae seu pleiones, 10 parts of Rhizoma Polygoni Cuspidati, 10 parts of Spora Lygodii, 10 parts of the Radixs Astragali, 5 parts of Herba Poae Sphondylodiss, 5 parts of Radix Curcumaes, 4 parts of Rhizoma Chuanxiongs, 1 part of Venenum Bufonis.
7, utilize the Orally applied anticancer agent of the described nano-magnetic microsphere preparation method preparation of claim 1, it is characterized in that: the used medicine of described Orally applied anticancer agent is the natural drug compound recipe, this prescription is made up of modern Chinese medicine and chemicals, described modern Chinese medicine accounts for the 80-98% of whole medicament composing prescription, described chemicals accounts for the 20-2% of whole medicament composing prescription, and the weight quota of the alcohol extract powder of the every kind of medicine of modern Chinese medicine compound recipe in the prescription is respectively: 30 parts of Herba Scutellariae Barbataes, 15 parts of Herba Violaes, 10 parts of Pseudobulbus cremastrae seu pleiones, 10 parts of Rhizoma Polygoni Cuspidati, 10 parts of Spora Lygodii, 10 parts of the Radixs Astragali, 5 parts of Herba Poae Sphondylodiss, 5 parts of Radix Curcumaes, 4 parts of Rhizoma Chuanxiongs, 1 part of Venenum Bufonis; The weight quota of the every kind of medicine of chemicals compound recipe in the prescription is respectively 80 parts of ifosfamides, 20 parts of paclitaxels.
8, utilize the Orally applied anticancer agent of the described nano-magnetic microsphere preparation method preparation of claim 1, it is characterized in that: the used medicine of described Orally applied anticancer agent is the chemicals compound recipe, the weight quota of every kind of medicine is respectively in the compound recipe: 50 parts of 5-flurouracil, 40 parts of ifosfamides, 1 part of 9 parts of paclitaxels and doxorubicin hydrochloride.
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| CNA2007103012477A CN101461784A (en) | 2007-12-17 | 2007-12-17 | Method for preparing nano magnetic microballoons and anticancer oral preparation prepared using the method |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102258791A (en) * | 2011-07-07 | 2011-11-30 | 山西大学 | Cyclodextrin/Fe3O4 magnetic nano composite and medicinal inclusion compound thereof |
| CN102258790A (en) * | 2011-07-07 | 2011-11-30 | 山西大学 | Clathrate compound of cyclodextrin/Fe3O4 magnetic nano compound and ibuprofen |
| CN102389399A (en) * | 2011-10-17 | 2012-03-28 | 东南大学 | Preparation method of drug-loaded microspheres capable of enhancing anticancer effect of paclitaxel by ultraviolet radiation and application thereof |
| CN103406080A (en) * | 2013-07-26 | 2013-11-27 | 大连工业大学 | Conjugation linoleic acid microcapsulate with wall material made of bacteria exopolysaccharide through complex coacervation method |
| CN104840425A (en) * | 2015-05-11 | 2015-08-19 | 刘先国 | Magnetic nano-microsphere preparation method and anti-cancer oral preparation prepared by using method |
| CN109091678A (en) * | 2018-08-21 | 2018-12-28 | 南开大学 | A kind of preparation method and applications of the super-molecule assembling body for the dual regulation inhibiting tumor invasion and diffusion |
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- 2007-12-17 CN CNA2007103012477A patent/CN101461784A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102258791A (en) * | 2011-07-07 | 2011-11-30 | 山西大学 | Cyclodextrin/Fe3O4 magnetic nano composite and medicinal inclusion compound thereof |
| CN102258790A (en) * | 2011-07-07 | 2011-11-30 | 山西大学 | Clathrate compound of cyclodextrin/Fe3O4 magnetic nano compound and ibuprofen |
| CN102389399A (en) * | 2011-10-17 | 2012-03-28 | 东南大学 | Preparation method of drug-loaded microspheres capable of enhancing anticancer effect of paclitaxel by ultraviolet radiation and application thereof |
| CN103406080A (en) * | 2013-07-26 | 2013-11-27 | 大连工业大学 | Conjugation linoleic acid microcapsulate with wall material made of bacteria exopolysaccharide through complex coacervation method |
| CN103406080B (en) * | 2013-07-26 | 2015-11-18 | 大连工业大学 | Complex coacervation prepares the CLA microcapsules that extracellular polysaccharide of bacteria is wall material |
| CN104840425A (en) * | 2015-05-11 | 2015-08-19 | 刘先国 | Magnetic nano-microsphere preparation method and anti-cancer oral preparation prepared by using method |
| CN109091678A (en) * | 2018-08-21 | 2018-12-28 | 南开大学 | A kind of preparation method and applications of the super-molecule assembling body for the dual regulation inhibiting tumor invasion and diffusion |
| CN109091678B (en) * | 2018-08-21 | 2022-01-28 | 南开大学 | Preparation method and application of double-regulation supermolecule assembly for inhibiting tumor invasion and diffusion |
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