CN1451378A - Antitumor drug erianin fat emulsion and preparing process thereof - Google Patents
Antitumor drug erianin fat emulsion and preparing process thereof Download PDFInfo
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Abstract
An antineoplastic medicine "fatty emulsion of Maolansu" is prepared from Maolansu, soybean oil, soybean phosphatide, glycerine and water for injection through preparing early emulsion, high-pressure homogenizing, regulating pH value, and sterilizing. Its advantages are high curative effect, slow releasing and low cost.
Description
Technical field
The present invention relates to a kind of " Maolansu " fat emulsion as antineoplastic medicine and preparation method thereof, belong to the field of Chinese medicines.
Technical background
Tumor is the disease of a class serious threat human health, according to statistics, total about more than 3,000 ten thousand people of all kinds of tumor patients in the whole world in 1999, in China more than 400 ten thousand people are arranged approximately, along with constantly increasing the weight of that the quickening of industrialization degree and water source and air ambient pollute, the sickness rate of malignant tumor just increases progressively with 3% annual increasing rate.
Drug therapy (chemotherapy) is present clinical cancer therapy one of the most effective means.The chemotherapeutic agent that is used for oncotherapy now has over one hundred kind, though these chemotherapeutic agents can be controlled the development of tumor to a certain extent, prolongs the life span of tumor patient, and cure rate is still very low.In addition, all these chemotherapeutic agents at present, its selectively acting is generally relatively poor, and is all very strong to toxic and side effects such as body hemopoietic system, liver, kidney, hearts, late tumor patient even beyond affordability.Therefore, still there are very big demand in good effect, medicine for treating tumor thing that toxic and side effects is low.
The hair orchid element is the bibenzyl chemical compound, its structural formula name be called 3-hydroxyl-4,3 ', 4 ', 5 '-the tetramethoxy bibenzyl, molecular weight 318, its English by name erianin or dihydrocombretastatin A-4 are dissolved in organic solvent, and be atomic water-soluble.Twentieth century beginning of the nineties, Cushman, people such as M. (Cushman, M. etc., J MedChem.1991,34,2579-2588) discover by the cell in vitro cultured method, the hair orchid element all has inhibitory action to the growth of the human body lung adenocarcinoma cell line A-549 of In vitro culture, breast cancer cell line mcf-7, colon cancer cell line HT-29, leukemia cell line MLM etc., its mechanism of action with suppress tubulin polymerization, to suppress that new vessels forms, vasoconstrictive reduces tissue blood flow's amount etc. relevant.Yet up to the present, also the list of discovery is the report of the antitumor drug of compositions with the hair orchid element or with the hair orchid element.
In addition, as mentioned above, the hair orchid element has the organic solvent of being dissolved in, atomic water-soluble physical property, and therefore, if be made into the injectable powder or the aqueous injection of water miscible oral formulations or injection, the consumption volume that is bound to is big, and clinical use is very difficult.Certainly, also the hair orchid element can be made the form of Setoglaucine salt earlier, reaching increases its dissolubility in water, again Setoglaucine salt is made the injectable powder or the aqueous injection of water miscible oral formulations or injection, do like this, though see feasiblely from technical standpoint, technology is comparatively complicated, and cost is also higher.The present invention is dissolved in the character of plant wet goods organic solvent according to the hair orchid element, be made into oil and the mixed uniformly lipomul of water energy, having solved not need be with the form of Setoglaucine salt, can be for oral or for injection, lipomul medicine easy to use but directly the hair orchid element is made.
Summary of the invention
The present invention includes two contents: (1) a kind of " Maolansu " fat emulsion as antineoplastic medicine; (2) a kind of preparation method of " Maolansu " fat emulsion as antineoplastic medicine.
One, a kind of " Maolansu " fat emulsion as antineoplastic medicine
Physicochemical property characteristics such as the present invention is dissolved in organic solvent, is slightly soluble in water according to the hair orchid element, and polarity is lower, and can bring into play the characteristics of its anti-tumor biological to greatest extent according to the pharmacodynamic study intravenously administrable, but it is prepared into the injection lipomul.
A kind of " Maolansu " fat emulsion as antineoplastic medicine of the present invention, it mainly comprises antitumor effective amount of actives hair orchid element, pharmaceutically useful vegetable oil, emulsifying agent, osmotic pressure regulator and water.The hair orchid element is dissolved in the vegetable oil.
Active component hair orchid element is the extract that extracts from the Chinese crude drug Herba Dendrobii, it can (application number be 03115752.1 by taking " extracting the method for hair orchid element in a kind of Herba Dendrobii ", the applying date is to have done detailed narration in the application for a patent for invention file on March 12nd, 2003) obtain, but this is not unique method and the unique source that obtains the hair orchid element.
The pharmaceutically useful vegetable oil of preparation lipomul generally is selected from soybean oil, Semen Maydis oil, Oleum sesami, olive oil, Semen Lini oil, safranine caul-fat and these oily mixture, also can use fatty acid triglyceride, vegetable oil is selected soybean oil for use in the embodiment of the invention.
Pharmaceutically useful emulsifying agent can be with soybean phospholipid or lecithin, and emulsifying agent is selected soybean phospholipid for use in the embodiment of the invention.
Pharmaceutically useful osmotic pressure regulator can be selected the mixture of glycerol, glucose, mannitol, sorbitol and these regulators for use, and what osmotic pressure regulator was selected for use in the embodiment of the invention is glycerol.
The consumption of each component of the plain lipomul of medicine hair orchid of the present invention and the general standard that quality should meet pharmacy.In order to guarantee that " Maolansu " fat emulsion as antineoplastic medicine of the present invention reaches the injection standard, its all components comprises active component hair orchid element, water, vegetable oil, emulsifying agent, osmotic pressure regulator and other materials, all should reach the injection standard simultaneously.
" the antitumor effective dose " of previously described active component hair orchid element is meant the amount that contains the hair orchid element that can treat tumor effectively in the plain lipomul of hair orchid.Since administration object difference, different and everyone the reaction difference of body weight to medicine, and this effective dose is also different.But from the angle of product, this effective dose depends on the concentration of hair orchid element in the product and gives the volume of product.The concentration of hair orchid element can change in suitable scope in the product, and the scope of concentration change depends on that the volume of the dissolubility of hair orchid element in used vegetable oil, dosage, administration and people are to the limit of the maximum tolerance of pharmaceutically acceptable vegetable oil and emulsifying agent soybean phospholipid or lecithin etc.In view of the above, the concentration of hair orchid element can be in the 1-3.8mg/ml scope in the plain lipomul of hair orchid of the present invention.In conjunction with patient's dosage, administration volume and people tolerance degree, be preferred concentration again with 2.0mg/ml to soybean phospholipid or lecithin and pharmaceutically acceptable vegetable oil.
In the component of " Maolansu " fat emulsion as antineoplastic medicine of the present invention, vegetable oil is the solvent of anti-tumor active ingredient hair orchid element, because vegetable oil kind is various, its polarity of different types of vegetable oil is had nothing in common with each other again, so the dissolubility of hair orchid element in different types of vegetable oil also has difference.In view of this, active component hair orchid element reaches " antitumor effective dose " in the plain lipomul of hair orchid in order to make, so can there be certain difference in different types of vegetable oil on amount ranges.In embodiments of the present invention, vegetable oil is selected soybean oil for use, and its reasonable volume should be between 100-250mg/ml, and preferable amount is 200mg/ml.
For guaranteeing the emulsion quality and the stability of the plain lipomul of hair orchid, in " Maolansu " fat emulsion as antineoplastic medicine of the present invention, the consumption of emulsifying agent and the consumption of vegetable oil should mate.In embodiments of the present invention, the proper ratio of the soybean phospholipid that soybean oil that vegetable oil is selected for use and emulsifying agent are selected for use is about 1: 0.06, and correspondingly, emulsifying agent coupling consumption is about 6-15mg/ml, and preferable amount is 12mg/ml.In addition, because different types of emulsifying agent emulsifying capacity has difference, also should be different to some extent on consumption.
In " Maolansu " fat emulsion as antineoplastic medicine component of the present invention, its effect of osmotic pressure regulator is that the osmotic pressure of " Maolansu " fat emulsion as antineoplastic medicine of the present invention is regulated in the normal physiological scope of the pure man.In general say that different osmotic pressure regulators is because its molecular size is different with polarity, even identical weight, the osmotic pressure that the different osmotic regulator is produced also can be different.Also must be noted that simultaneously, in " Maolansu " fat emulsion as antineoplastic medicine of the present invention, other component (as anti-tumor active ingredient, vegetable oil, emulsifying agent etc.) also produces certain influence to osmotic pressure, in view of above reason, the consumption fibrous root of every kind of osmotic pressure regulator is decided according to the molecular size of the selected osmotic pressure regulator of the consumption of other component in the plain lipomul of hair orchid and this kind and polarity power; In embodiments of the present invention, for the osmotic pressure that makes " Maolansu " fat emulsion as antineoplastic medicine of the present invention in people's normal physiological scope, selected its suitable amounts of osmotic pressure regulator glycerol is 18-25mg/ml, preferable amount is 22mg/ml.
In sum, the general prescription of the plain lipomul of medicine hair orchid of the present invention is:
The plain 1-3.8g of active component hair orchid
Soybean oil 100-250g
Soybean phospholipid 6-15g
Glycerol 25-18g
Water for injection adds to 1000ml
Its optimizing prescriptions is:
The plain 2.0g of active component hair orchid
Soybean oil 200g
Soybean phospholipid 12g
Glycerol 22g
Water for injection adds to 1000ml
In " Maolansu " fat emulsion as antineoplastic medicine of the present invention, the anti-tumor active ingredient that can also contain other, can improve curative effect whereby, reduce toxic and side effects and enlarge range of application, as comprise known anti-tumor active ingredients such as paclitaxel, carboplatin, cyclophosphamide, fluorouracil, amycin.
In addition, in " Maolansu " fat emulsion as antineoplastic medicine of the present invention, also can add antioxidant such as vitamin E, ascorbic acid etc.; Also can add increases the surperficial zeta potential of breast grain, improves the stabilizing agent of the plain lipomul stability of hair orchid, as oleic acid, cholic acid, deoxycholic acid and their corresponding salt thereof.
" Maolansu " fat emulsion as antineoplastic medicine of the present invention can be by injection or oral mode administration, as tumor treatment.The professional and technical personnel can be according to patient's practical situation, according to the concentration of hair orchid element in the plain lipomul of hair orchid and patient's per weight dosage (as 20mg/kg) or unit are dosage (as 100mg/m
2), be easy to determine the dosage of administration.
" Maolansu " fat emulsion as antineoplastic medicine of the present invention can get with following described prepared.
Two, a kind of preparation method of " Maolansu " fat emulsion as antineoplastic medicine
Its content of the preparation method of " Maolansu " fat emulsion as antineoplastic medicine of the present invention comprises prescription and technology, and it is write out a prescription as mentioned above, and its preparation technology comprises the steps:
(1) it is standby to take by weighing each component by prescription; Active component hair orchid element is dissolved in the vegetable oil (water-bath in case of necessity heat dissolving), oil-phase solution;
(2) water for injection of emulsifying agent with an amount of preheating is dissolved fully, add osmotic pressure regulator again, mix homogeneously gets aqueous phase solution;
(3) in the aqueous phase solution of above-mentioned preparation, feed ultrapure nitrogen, open the blender high-speed stirred,, stirred again after dropwising 3-5 minute, get milky colostrum comparatively uniformly while stirring to the oil-phase solution that wherein drips above-mentioned preparation.
(4) colostrum is added in the high pressure homogenizer, open air pump, regulate high pressure homogenizer pressure, treat to begin high pressure homogenize after the pressure stability, collect emulsion through high pressure homogenize to 83-138MPa; It is left standstill room temperature, add water for injection to the total amount of writing out a prescription, mix homogeneously promptly gets the plain lipomul of hair orchid of milky homogeneous.
(5) regulate its pH value to 8.5-9.5 with aqueous slkali; Under the condition of logical ultrapure nitrogen, filtration, packing, sealing, last moist heat sterilization, but promptly get the hair orchid element lipomul finished product of injection.
In the preparation process of the above-mentioned oil-phase solution that contains the hair orchid element, in order to save time, can take the mode of heating in water bath to quicken the dissolving of hair orchid element in pharmaceutically acceptable vegetable oil in case of necessity, bath temperature can be between 60-80 ℃.
Above-mentioned emulsifying agent soybean phospholipid and lecithin are in heating or be exposed to as easy as rolling off a log oxidation in the air, for avoiding or reduce the oxidation of emulsifying agent, in the preparation process of the plain lipomul of above-mentioned hair orchid, should begin all to need under the condition of logical nitrogen, carry out from step (2) preparation aqueous phase solution at least to the preceding operation of step (5) packing.
In the present invention, the preparation of above-mentioned colostrum can be adopted high-speed mixing method, and mixing speed is between 8000-20000 rev/min, and preferred mixing speed is between 15000-18000 rev/min.
When high pressure homogenize, homogenization pressure can be in the 83-138Mpa scope, and preferred pressure is between 96-120Mpa.This homogenizing method is not got rid of the method that adopts two step high pressure homogenize, and about each parameters such as homogenization pressure of two step high pressure homogenize, those skilled in the art is easy to this adjust.
The specific embodiment
The invention will be further described below in conjunction with embodiment, but the present invention does not limit in these embodiments.
Embodiment 1
Take by weighing the plain 2.0g of hair orchid, injection soybean oil 200g, injection soybean phospholipid 12g, glycerol for injection 22g, water for injection is an amount of.The hair orchid element is joined in the injection soybean oil, place 70 ℃ water bath with thermostatic control water-bath, it is dissolved fully, get oil-phase solution; The injection soybean phospholipid is dissolved fully with the water for injection that is preheated to 70 ℃ in right amount, add glycerol for injection again, mix homogeneously gets aqueous phase solution; In above-mentioned aqueous phase solution, feed ultrapure nitrogen, open blender, stir, to wherein dripping the above-mentioned oil-phase solution for preparing, continue again after dropwising to stir 5 minutes while stirring, get milky colostrum comparatively uniformly with 18000 rev/mins of rotating speeds.
Again colostrum solution is joined in the hopper of high pressure homogenizer, open the air pump switch, regulate high pressure homogenizer pressure, treat the laggard horizontal high voltage homogenizing of pressure stability to 110MPa; Collection is left standstill room temperature through the emulsion of high pressure homogenize with it, adds water for injection to 1000ml (the about 769ml of actual used water in this enforcement), and mix homogeneously promptly gets the plain lipomul of hair orchid of milky homogeneous.
In the plain lipomul of the above-mentioned hair orchid that makes, drip the sodium hydroxide solution of 0.1M, regulate its pH value to 8.5; Filtration under the condition of logical ultrapure nitrogen, is sub-packed in it in infusion bottle, and the Zha Gai sealing places the interior 120 ℃ of sterilizations of moist heat sterilizer 30 minutes, but gets the plain lipomul finished product of hair orchid of injection.
Embodiment 2,3
Processing step and the example 1 of embodiment 2,3 are identical, in its prescription in each component and consumption, the technology parameter as shown in table 1:
Component utilized, component and pressure parameter among each embodiment of table 1
| Embodiment 1 | Embodiment 2 | Embodiment 3 | |||
| Prescription | Active component | The plain 2g of hair orchid | The plain 1g of hair orchid | The plain 3.8g of hair orchid | |
| Vegetable oil | Soybean oil 200g | Soybean oil 100g | Soybean oil 250g | ||
| Emulsifying agent | Soybean phospholipid 12g | Soybean phospholipid 6g | Soybean phospholipid 15g | ||
| Osmotic pressure regulator | Glycerol 22g | Glycerol 25g | Glycerol 18g | ||
| Water | Add to 1000ml | With example 1 | With example 1 | ||
| Homogenizer pressure | 110MPa | 83MPa | 138MPa | ||
| Remarks | Preferred value | Lower limit | Higher limit | ||
In the above-described embodiments, used injection soybean oil, oil solvents such as also available injection Semen Maydis oil, Oleum sesami, olive oil, Semen Lini oil, safranine caul-fat, fatty acid triglyceride and composition thereof are replaced; The also available injection lecithin of used injection soybean phospholipid or both mixture are replaced.
The plain lipomul of the hair orchid of adopting the present invention to make, its quality outward appearance homogeneous after testing, it is aqueous to be creamy white, PH is 6.8-7.3 (pH value after the sterilization), osmotic pressure accounts for 80% below the particle diameter 1um in people's normal physiological range, particle diameter not detecting more than 5um, aseptic, quality index such as endotoxin meet the Pharmacopoeia of People's Republic of China relevant regulations.Stability test shows steady quality under the room temperature of 3 months accelerated tests and a year.
Below further illustrate the beneficial effect of the plain lipomul of medicine hair orchid of the present invention by testing example, these tests comprise antitumor activity in vitro and anti-tumor in vivo test.[test example 1] in vitro method antitumor test: 1, test material:
The plain lipomul (Tianhuang Pharmaceutical Co., Ltd., Zhejiang provides) of test drug hair orchid; Positive reference substance amycin (Zhejiang Haizheng Pharmaceutical Co company limited product); Tumor cell line: leukemia cell line HL-60, lung adenocarcinoma cell line A-549, colon cancer cell line HCT-116, hepatocellular carcinoma cell strain BEL-7402, breast cancer cell line mcf-7.2, test method:
Respectively the above-mentioned tumor cell line of some is seeded in the culture plate in 96 holes, the suspension growth cell is dosing immediately after inoculation,, the adherent growth cell inoculation cultivate treated in 24 hours its adherent after dosing again.The plain lipomul of test drug hair orchid is established 8 or 10 activities, and each concentration is established 8 multiple holes.Other establishes acellular zeroing hole, corresponding solvent as negative control hole and amycin positive control hole.
The suspension growth cell adopts mtt assay to measure.Behind the drug effect 48 hours, and adding MTT working solution (5mg/ml, Sigma), every hole 20ul; 37 ℃ act on 4 hours, add three liquid (10%SDS-5% isobutanol-0.01mol/L HCl) again; 37 ℃ of effects are after 12-20 hour, measure the OD value on microplate reader in 570nm wavelength place; The adherent growth cell adopts srb assay to measure.Behind the drug effect 72 hours, the culture fluid that inclines adds 10%TCA, and every hole 100ul fixes 1 hour for 4 ℃; The fixative that inclines is with distillation washing 5 times, natural drying.Add again the SRB working solution (4mg/ml, Sigma), every hole 100ul, room temperature dyeing 15 minutes discards dye liquor, washes 5 times natural drying with 1% glacial acetic acid.Add the Tris buffer at last, every hole 150ul shakes up, and measures the OD value on the microplate reader in 515nm wavelength place.Calculate the cell proliferation growth inhibition ratio by following formula:
Suppression ratio (%)=(OD value
Contrast is empty-OD value
Dosing holes)/OD value
Contrast is empty* 100%
Adopt LOGIT method calculation of half inhibitory concentration IC
50Value.With IC
50Value is as the final index of the ability of inhibition.3, result of the test:
The proliferate of the external human tumor cells to 5 strain different tissue sources of the plain lipomul of hair orchid all presents stronger antitumor action (seeing the following form), and is wherein the strongest to the effect of human leukemia cell HL-60 growth inhibited, IC
50Value is 0.0025ug/ml; IC is taken second place in tumor cell A-549 effect to the respiratory system source
50Value is 0.012ug/ml; To the growth inhibited effect of the tumor cell HCT-116 in gastrointestinal tract source again time, IC
50Value is 0.05ug/ml; A little less than the effect slightly to breast carcinoma and hepatocarcinoma, IC
50Value is respectively 0.94ug/ml and 1.07ug/ml.Result of the test shows that also the plain lipomul antitumor action of hair orchid has selectivity to a certain degree.
Table 1, the plain lipomul of hair orchid external proliferate suppression ratio and IC to 4 strain human tumor cells
50Proliferate suppression ratio (%) IC of value cell strain variable concentrations hair orchid element (ug/ml)
50Value
21 0.5 0.25 0.125 0.0625 0.031 0.016 0.008 0.004 (ug/ml) HL-60 does not survey 68.9 66.8 64.5 64.5 52.6 65.2 63. 144.1 0.0025A-549 and does not survey 94.1 96.0 90.4 88.4 86.4 75.4 37.8 12.1 0.012HCT-116 85.4 85.2 81.4 78.1 69.0 46.8 25.8 0.0 and do not survey 0.05MCF-7 71.7 45.9 36.0 19.9 17.8 11.8 6.9 12.0 and do not survey 0.94
Table 2, the plain lipomul of hair orchid external proliferate suppression ratio and IC to human hepatoma cell strain BEL-7402
50Proliferate suppression ratio (%) IC of value cell strain variable concentrations hair orchid element (ug/ml)
50Value
20??????10????????5???????2.5??????1.25????0.625???0.312???0.156??(ug/ml)BEL-7402??98.5????98.5????97.6????87.7????91.2????62.7?????4.3???????0?????1.07
Table 3, positive control drug amycin are to the proliferate IC of 5 strain human tumor cells
50Value cell strain HL-60 A-549 HCT-116 BEL-7402 MCF-7IC
50Value (mg/ml) 0.02 0.016 0.02 0.06 16.04, conclusion (of pressure testing):
The proliferate of the external human tumor cells to leukemia and different tissue sources of the plain lipomul of hair orchid has stronger inhibitory action, and demonstrates certain selectivity.[test example 2] intracorporal method antitumor test: 1, test material
The plain lipomul (Tianhuang Pharmaceutical Co., Ltd., Zhejiang) of investigational agent hair orchid, positive control drug Cyclophosphamide for injection (Hua Lian, Shanghai pharmacy group product), cisplatin for inj (Shandong Qilu Pharmaceutical Factory product); Tumor source: mice S180 sarcoma, human body pulmonary carcinoma (all having pharmacological room of Shanghai Institute of Pharmaceutical Industry to go down to posterity provides); Laboratory animal: Kunming mouse (quality certification number is provided by Chinese Academy of Sciences's Shanghai Experimental Animal Center: Shanghai is moving closes the card word No. 107), nude mice (quality certification number is provided by Chinese Academy of Sciences's Shanghai medicine: moving the closing in Shanghai is demonstrate,proved No. the 122nd, word).2, test method
Mice S180 sarcoma animal subcutaneous vaccination model: get eugonic S180 tumor under the aseptic condition, be diluted to cell homogenates with the normal saline of appropriate amount, concentration is 1-2 * 10
7/ ml in Kunming mouse axil subcutaneous vaccination 0.2ml/ only, begins administration next day.The plain lipomul of hair orchid divides three dosage groups, and every day, tail vein injection was 1 time, successive administration 15 days; Two groups of negative blank and positive controls are established in contrast, and negative blank group mice gives the blank Emulsion of tail vein injection equal volume every day, successive administration 15 days.The positive controls mice gives tail vein injection cyclophosphamide, successive administration 7 days every day.Each treated animal is put to death in 3 week backs, cuts open to get tumor and weigh, and calculates tumor control rate by following formula:
Tumor control rate (%)=[(the average tumor of the average tumor weight-administration of matched group group is heavy)/average tumor of matched group is heavy] * 100%.
Human body pulmonary carcinoma A549 xenotransplantation is in nude mice model: get the A549 human body pulmonary carcinoma third generation tumor tissues that grows in nude mice under the aseptic condition, become cell homogenates with normal saline by 1: 6 dilution proportion, concentration is 1-2 * 10
7/ ml in nude mice axil subcutaneous vaccination 0.2ml/ only, begins administration next day.The plain lipomul of hair orchid divides three dosage groups, and every day, tail vein injection was 1 time, successive administration 15 days.Two groups of negative blank and positive controls are established in contrast, and negative blank group mice gives the blank Emulsion of tail vein injection equal volume every day, successive administration 15 days.The positive controls mice gives tail vein injection cisplatin, successive administration 7 days every day; Each treated animal is put to death in 3 week backs, cuts open to get tumor and weigh, and calculates by the formula of aforementioned calculation tumor control rate.3, result of the test
Result of the test shows that the plain lipomul of high dose hair orchid is 54.45% to animal subcutaneous vaccination mice S180 sarcoma model tumor growth proliferation inhibition rate, is 59.36% to xenotransplantation in the tumor growth proliferation inhibition rate of nude mice human body pulmonary carcinoma A549 tumor model.Find also in the process of the test that plain each the test group mice activity of lipomul of hair orchid, diet, hair color are all normal, weight increase.Prompting hair orchid element has significant inhibitory effect to growth of tumor propagation, and does not have overt toxicity.Concrete outcome sees Table 4, table 5:
Table 4, the plain lipomul of hair orchid are to the heavy tumour inhibiting rate of mice S180 sarcoma (subcutaneous vaccination) curative effect sample dose dosage regimen number of animals (only) the weight of animals tumor
(mg/kg) begin/begin eventually/eventually, (g) X ± SD, (g), (%) EN 10 iv * 15qd 10/10 18.7/24.0 1.83 ± 0.19 34.88 EN 50 iv * 15qd 10/10 18.7/25.9 1.44 ± 0.16 48.75 EN 100 iv * 15qd 10/10 18.5/26.2 1.28 ± 0.18 54.45 endoxan 30 ip * 7qd 10/10 18.6/24.0 0.30 ± 0.16 89.57 female part contrast coordinative solvent iv * 15qd, 20/20 18.8/26.5 2.81 ± 0.34
Table 5, the plain lipomul of hair orchid are to the heavy tumour inhibiting rate of curative effect sample dose dosage regimen number of animals (only) the weight of animals tumor of human body pulmonary carcinoma A549 heteroplastic transplantation model
(mg/kg) begin/begin eventually/whole (%) EN 50 iv * 15qd 6/6 19.5/24.0 0.82 ± 0.15 56.15 EN 100 iv * 15qd 6/6 19.0/23.7 0.78 ± 0.12 58.29 EN 200 iv * 15qd 6/6 19.3/24.2 0.76 ± 0.07 59.36 cis-platinum 30 ip * 7qd 6/6 19.3/19.8 0.22 ± 0.08 88.24 negative control coordinative solvent iv * 15 qd, 12/12 19.1/23.8 1.87 ± 0.224, conclusion of (g) X ± SD (g)
The plain lipomul of hair orchid has remarkable antitumor effect, and toxicity is lower.According to the characteristics of general lipomul pharmaceutics, antitumor drug hair orchid rope lipomul of the present invention also has slow release, targeting, effects such as energy is provided for body.
Claims (6)
1, a kind of " Maolansu " fat emulsion as antineoplastic medicine is characterized in that it mainly comprises pharmaceutically useful vegetable oil, emulsifying agent, osmotic pressure regulator, water and is dissolved in antitumor effective amount of actives hair orchid element in the vegetable oil.
2, a kind of " Maolansu " fat emulsion as antineoplastic medicine as claimed in claim 1 is characterized in that described vegetable oil is selected from the mixture of soybean oil, Semen Maydis oil, Oleum sesami, olive oil, Semen Lini oil, safranine caul-fat and these vegetable oil; Emulsifying agent is selected from soybean phospholipid, lecithin; Osmotic pressure regulator is selected from the mixture of glycerol, glucose, sorbitol and these regulators.
3, a kind of " Maolansu " fat emulsion as antineoplastic medicine as claimed in claim 2 is characterized in that described vegetable oil is a soybean oil, and emulsifying agent is a soybean phospholipid, and osmotic pressure regulator is a glycerol.
4, as claim 2,3 described a kind of " Maolansu " fat emulsion as antineoplastic medicine, it is characterized in that its prescription is:
The plain 1.0-3.8g of active component hair orchid
Soybean oil 100-250g
Soybean phospholipid 6-15g
Glycerol 25-18g
Water for injection adds to 1000ml
5, a kind of " Maolansu " fat emulsion as antineoplastic medicine as claimed in claim 4 is characterized in that its prescription is:
The plain 2.0g of active component hair orchid
Soybean oil 200g
Soybean phospholipid 12g
Glycerol 22g
Water for injection adds to 1000ml
6, the preparation method of a kind of " Maolansu " fat emulsion as antineoplastic medicine as claimed in claim 1, it is characterized in that following steps are arranged: (1) is dissolved in antitumor effective amount of actives hair orchid element in the pharmaceutically useful vegetable oil (water-bath in case of necessity heat dissolving), oil-phase solution;
(2) an amount of emulsifying agent is added proper amount of water for injection and make it to dissolve fully, add an amount of osmotic pressure regulator again, mix homogeneously gets aqueous phase solution;
(3) in aqueous phase solution, feed ultrapure nitrogen, carry out high-speed stirred,, after dropwising, restir 3-5 minute, promptly get white colostrum comparatively uniformly while stirring to the oil-phase solution that wherein splashes into aforementioned preparation with blender;
(4) colostrum is added in the high pressure homogenizer, use homogenization pressure between 83-138MPa, regulate homogenizer pressure, treat to begin high pressure homogenize after the pressure stability, collect emulsion, be the plain lipomul of hair orchid of white homogeneous through high pressure homogenize; Leave standstill to room temperature, add water for injection to the total amount of writing out a prescription;
(5) pH value of regulating the plain lipomul of above-mentioned hair orchid with aqueous slkali is between the 8.5-9.5, filters, the embedding sterilization, is the plain lipomul finished product of hair orchid.
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| CN1225242C CN1225242C (en) | 2005-11-02 |
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| CN (1) | CN1225242C (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007124465A2 (en) | 2006-04-20 | 2007-11-01 | Amgen Inc. | Stable emulsion formulations |
| CN101062043B (en) * | 2006-04-30 | 2011-06-08 | 浙江天皇药业有限公司 | Application of 3, 4, 5, 4'-tetramethyl diphenylethane-3'-O-disodium phosphate in the anti-cancer medicine and the transferring medicine thereof |
| CN109602707A (en) * | 2019-02-03 | 2019-04-12 | 隋新兵 | Erussian liposome composition and preparation method thereof |
| CN109846822A (en) * | 2019-03-21 | 2019-06-07 | 于波涛 | Erussian nanometer formulation and its preparation method and application |
| CN112618558A (en) * | 2020-09-23 | 2021-04-09 | 浙江工业大学 | Erianin-adriamycin-containing double-drug co-carried liposome as well as preparation and application thereof |
-
2003
- 2003-05-21 CN CNB031170692A patent/CN1225242C/en not_active Expired - Fee Related
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007124465A2 (en) | 2006-04-20 | 2007-11-01 | Amgen Inc. | Stable emulsion formulations |
| WO2007124465A3 (en) * | 2006-04-20 | 2008-04-10 | Amgen Inc | Stable emulsion formulations |
| AU2007240317B2 (en) * | 2006-04-20 | 2012-11-29 | Amgen Inc. | Stable emulsion formulations |
| US8779004B2 (en) | 2006-04-20 | 2014-07-15 | Amgen, Inc. | Stable emulsion formulations |
| CN101062043B (en) * | 2006-04-30 | 2011-06-08 | 浙江天皇药业有限公司 | Application of 3, 4, 5, 4'-tetramethyl diphenylethane-3'-O-disodium phosphate in the anti-cancer medicine and the transferring medicine thereof |
| CN109602707A (en) * | 2019-02-03 | 2019-04-12 | 隋新兵 | Erussian liposome composition and preparation method thereof |
| CN109602707B (en) * | 2019-02-03 | 2021-09-03 | 隋新兵 | Erianin liposome composition and preparation method thereof |
| CN109846822A (en) * | 2019-03-21 | 2019-06-07 | 于波涛 | Erussian nanometer formulation and its preparation method and application |
| CN112618558A (en) * | 2020-09-23 | 2021-04-09 | 浙江工业大学 | Erianin-adriamycin-containing double-drug co-carried liposome as well as preparation and application thereof |
| CN112618558B (en) * | 2020-09-23 | 2022-04-19 | 浙江工业大学 | Erianin-adriamycin-containing double-drug co-carried liposome as well as preparation and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1225242C (en) | 2005-11-02 |
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