CN101249070A - 2-methoxyestradiol intravenous nanoemulsion - Google Patents

Abstract

The invention relates to 2-methoxyestradiol intravenous nanoemulsion, which is composed of 0.05%-0.5% of 2-methoxyestradiol, 5%-50% of oil for injection and 0.05% of emulsifier ～5%, isotonic regulator 2%～6%, pH regulator and the rest are made of water for injection, in which 2-methoxyestradiol and emulsifier are dissolved in organic solvent, and then evaporated to dryness under reduced pressure to remove all organic substances. Solvent, to obtain liquid crystal or solid dispersion of drug emulsifier, then add filtered oil for injection or filtered water phase mixture to disperse, stir to obtain colostrum; then pass through a high-pressure milk homogenizer, adjust the pH value with a pH regulator, Finally, add water for injection to the full amount; then filter, package, sterilize, flush with hot water and cool to room temperature, the present invention is a nanoemulsion composition suitable for intravenous administration with sustained release and targeting ability in vivo , can overcome the defects of oral preparations, is safe and reliable, is a great innovation in medicine, and has huge social and economic benefits.

Description

2-methoxyestradiol intravenous nanoemulsion

1. Technical field

The invention relates to the field of medicine, in particular to a nanoemulsion composition composed of a water-insoluble anticancer drug 2-methoxyestradiol and an auxiliary material that can be physiologically accepted by veins: 2-methoxyestradiol intravenous nanoemulsion.

2. Background technology

2-methoxyestradiol (1,3,5-triene-2,3,17β-trihydroxy-2-methyl ether sterol) is a physiological metabolite of estradiol in vivo (Schumacher G et al. J Cancer Res ClinOncol.127: 405-410, (2001)), has obvious anti-tumor activity, and its anti-cancer mechanism may be the induction of tumor and endothelial cell apoptosis (Lin HL et al. Cancer. 92: 500-509 (2001) ), also has anti-tumor angiogenesis (Figg WD et al. Invest New Drug. 20: 183-194 (2002)) and its ability to inhibit the proliferation of tumor cells (Kumar AP et al. Carcinog. 31: 111-124 (2001)) . Some scholars have also found that 2-methoxyestradiol inhibits cell proliferation in a time-dose-dependent manner in the study of the effect of 2-methoxyestradiol on myeloma cells, and its inhibitory effect is the highest at 10 μmol/L. Strong (Dingli D et al. Clin Cancer Res. 8: 3948 ~ 3954 (2002)), this requires that 2-methoxyestradiol needs to reach an effective blood drug concentration on the one hand when it is used clinically, and requires at the same time The body can maintain an effective blood drug concentration for a long time. However, the Phase I clinical study results of 2-methoxyestradiol showed that oral administration of 2-methoxyestradiol was irregular, and there was no correlation between pharmacokinetic parameters and dosage (James J et al., Invest New Drugs, 25 : 41-48 (2006)). Therefore, the injection form of 2-methoxyestradiol can solve the defects of its oral preparation.

在使用过程中还是出现较高的临床过敏反应，使临床治疗的顺应性差。2-Methoxyestradiol is a poorly soluble drug in water, and its solubility in water is less than 5 mg/L. The injection of this type of drug can be an injection suspension, which requires the drug to have a high pharmacological Active, that is, there is a small dosage, and it can only be injected intramuscularly and subcutaneously, but the conventional dosage of 2-methoxyestradiol needs to reach more than 400mg; the second is to use organic solvents as solvents, or use ethanol Polyoxyethylene hydrogenated castor oil is added to the solvent as a solubilizer. The fatal flaw of the injection solution solubilized by organic solvents and surfactants is that it is easy to cause hemolysis and allergic reactions, and lacks sustained release and targeting, such as products already on the market It is clearly stipulated that corticosteroids and antihistamines should be used for desensitization before clinical use.

Higher clinical allergic reactions still occur during use, which makes the compliance of clinical treatment poor.

3. Contents of the invention

For above-mentioned situation, in order to overcome its shortcoming, the object of the present invention is exactly to constitute the drug 2-methoxyestradiol and bioacceptable adjuvant that can be used for intravenous injection together, have better biocompatibility A 2-methoxyestradiol intravenous nanoemulsion with certain slow-release ability and targeting. Its solution technical scheme is: the present invention is by weight volume ratio 2-methoxyestradiol 0.05%～0.5% (W/V), injection oil 5%～50%, emulsifier 0.05%～5%, 2%～6% of isotonic regulator, pH regulator and balance are made of water for injection [weight-to-volume ratio refers to solid matter in grams (g), liquid matter in milliliter (ml), i.e. W/V, The same below], wherein first 0.05% to 0.5% of 2-methoxyestradiol and 0.05% to 5% of emulsifier are dissolved in an organic solvent, and then evaporated to dryness under reduced pressure to remove the organic solvent to obtain the liquid crystal state of the drug emulsifier or Solid dispersion, then add 5% to 50% of oil for injection filtered by a 0.22 μm microporous membrane or 5% to 50% of an aqueous phase mixture filtered by a 0.22 μm microporous membrane (the aqueous phase mixture is composed of an emulsifier in a weight-to-volume ratio 0.05% to 5%, isotonic regulator 2% to 6%, and the balance is mixed with water for injection) to disperse and stir to obtain colostrum; The size of the nanoemulsion is related to the uniformity), the operating pressure is 5k~18k psi, the pH value is adjusted to 5.5~8.0 with a pH regulator, and finally add water for injection to the full amount; then filter through a 0.45μm microporous membrane to purify the nitrogen flow protection Filling and packaging, autoclaving at 121°C for 20 minutes, flushing with hot water and gradually cooling to room temperature to obtain the present invention. Tests show that the present invention is a nanoemulsion composition suitable for intravenous administration with slow-release ability and targeting ability in vivo, which can overcome the defects of oral preparations, and is safe and reliable. It is successfully developed and is a medical innovation. A major innovation with enormous social and economic benefits.

4. Specific implementation

The specific implementation of the present invention will be described in detail below in conjunction with the examples.

The nanoemulsion of the composition of the present invention consists of 0.05%～0.5% (W/V) of 2-methoxyestradiol in weight to volume ratio (W/V), 5%～50% of oil for injection, and 0.05%～5% of emulsifier. %, 2% to 6% of isotonic regulator, pH regulator and the rest are made of water for injection, of which 0.05% to 0.5% of 2-methoxyestradiol and 0.05% to 5% of emulsifier are used as organic solvents Dissolve, then evaporate to dryness under reduced pressure to remove all organic solvents to obtain the liquid crystal or solid dispersion of the drug emulsifier, then add 5% to 50% of oil for injection filtered through a 0.22 μm microporous membrane or filter through a 0.22 μm microporous membrane 5% to 50% of the aqueous phase mixture is dispersed, stirred to obtain colostrum; and then passed through the high-pressure homogenizer for more than three times (the number of times through the high-pressure homogenizer is related to the size and uniformity of the final nanoemulsion), and the operating pressure is 5k to 18k psi, use a pH regulator to adjust the pH value to 5.5-8.0, and finally add water for injection to the full amount; then filter through a 0.45 μm microporous membrane, purify the nitrogen flow to protect the filling package, and use a rotary autoclave at 121 ° C to sterilize for 20 Minutes, the sterilization is completed, the hot water is poured and gradually cooled to room temperature, and the present invention is obtained.

Said oil for injection in the present invention can be soybean oil, olive oil, sesame oil, safflower oil, cottonseed oil, saffron oil, corn oil, javanica oil, some medium-chain oils etc. can be the oil that intravenous injection is physiologically acceptable Any one of them or a mixture of two or three thereof, its content in the composition is 5% to 50% of the total volume of the composition, preferably 15% to 30%.

Said emulsifier in the present invention can be phospholipid or poloxamer or the mixture of both, and the content in composition is 0.05%～5%, preferably 0.5%～4%, wherein phospholipid is in composition The content in the total volume is 0.05% to 5%, preferably 0.5% to 3%; the content of poloxamer in the total volume of the composition is 0.05% to 5%, preferably 0.1% to 1%; if it is a mixture of the two, its The weight ratio of phospholipid to poloxamer is 10:1-1:5, preferably 5:1-2:1, and the content is 0.05%-5% of the total volume of the composition.

The phospholipids mentioned in the present invention include natural phospholipids, semi-synthetic phospholipids and artificial fully synthetic phospholipids, which can be soybean lecithin, egg yolk lecithin, soybean hydrogenated phospholipid, hydrogenated egg yolk lecithin, dipalmitoyl phospholipid, distearoyl phosphatidylethanolamine , polyethylene glycol-distearylethanolamine, etc., and any phospholipids modified by special modifications, such as phospholipids modified by monoclonal antibodies, phospholipids modified by galactosyl, phospholipids modified by special peptides, etc. One, also can be the mixture of two or more phospholipids of different properties, such as the mixture of soybean lecithin and polyethylene glycol-distearylethanolamine of long-circulation function, soybean hydrogenated phospholipid and long-circulation function of polyethylene glycol Ethylene glycol-distearylethanolamine mixture.

Said phospholipid and the phospholipid ratio of long circulation function are 1%～99%: 1%～99%, better with 80%～98%: 20%～2%, preferred 90%～95%: 10%～5% %.

Said poloxamer includes multiple models, such as poloxamer-188, poloxamer-338, poloxamer-407, etc. can be used as intravenous physiologically acceptable models, wherein poloxamer- 188 is optimal.

The 2-methoxyestradiol mentioned in the invention is the target drug, and the amount in the composition is 0.05% to 0.5% (W/V) by weight and volume, preferably 0.1% to 0.3% (W/V).

Said isotonic regulator in the present invention can be glucose, sorbitol, glycerin and any one in the kind that can be accepted physiologically by intravenous injection, and its consumption needs to be regulated according to the osmotic pressure size in the composition, with composition In terms of total volume and weight percentage: the consumption of glucose is generally 3% to 5%, the consumption of sorbitol is generally 3% to 6%, and the consumption of glycerin is generally 2% to 3%.

Said pH regulator in the present invention is the acid-base that can be accepted by physiology in vein, can be hydrochloric acid or sodium hydroxide, is used for regulating the pH value of composition nanoemulsion, and consumption is as the criterion so that its pH value reaches 5.5-8.0 .

Said organic solvent among the present invention can be chloroform or acetone, and consumption is advisable with fully dissolving 2-methoxyestradiol and emulsifier.

The composition of the present invention contains phospholipids. Due to well-known reasons, the composition is preferably protected by a purified nitrogen flow during the preparation process, and the sterilization temperature is as low as possible and the sterilization time is as short as possible.

The particle size of the nano-emulsion of the composition of the present invention is related to the emulsifier consumption, the variety and the number of times passed through the high-pressure homogenizer. Generally, the average particle diameter of one pass through the high-pressure homogenizer is about 600nm, and the average particle diameter after passing through the high-pressure homogenizer for three times is less than 300nm, the average particle diameter of the final product obtained is less than 300nm, the particles greater than 1 μm are less than 1%, and no particles greater than 5 μm have been detected; the composition has a surface potential of -5mV～-50mV according to the amount and variety of the emulsifier used (also It is called Zeta potential); when the composition is placed at room temperature, the size of the milk droplet is stable, and the Zeta potential is stable. The particle size becomes larger and the Zeta potential decreases; the pH value of this composition varies slightly depending on the type and amount of injection oil used, and the type and amount of emulsifier, but it is generally in the range of 5.5 to 8.0, suitable for intravenous injection. The maximum pH value shall not exceed 9.0.

The present invention can also be given by the following examples, but is not limited to the examples.

Example 1

Weigh 200 mg of 2-methoxyestradiol and 2.0 g of soybean lecithin, dissolve them in 5 ml of chloroform, evaporate to dryness under reduced pressure with a rotary thin-film evaporator, and remove the chloroform to form a drug liquid crystal film. 20g of soybean oil, shake to disperse the liquid crystal film, add 4% glucose solution filtered through a 0.22μm microporous membrane to 100ml, stir to form colostrum, and then pass through the micro-jet high-pressure milk homogenizer three times, the operating pressure is 17k psi , use 0.1Mol/L hydrochloric acid or 0.1Mol/L sodium hydroxide to adjust the pH value to 5.5-8.0, filter through a 0.45μm microporous membrane, purify nitrogen flow protection, fill and package, and sterilize with a rotary autoclave at 121°C After 20 minutes, rinse with hot water and gradually cool to room temperature.

The product of this embodiment, the average particle diameter 240nm, Zeta potential-35mV is measured by the laser scattering particle measuring instrument; Negative; use red blood cell suspension to measure its hemolytic property, no red blood cell hemolysis and red blood cell aggregation phenomenon were seen in the test product within 3 hours; the release results in vitro are shown in Table 1, indicating that it has sustained release ability; the distribution results in mice are shown in Table 2, Demonstrated ability to target.

Example 2

Weigh 150 mg of 2-methoxyestradiol and 1880.9 g of poloxamer, dissolve in 5 ml of chloroform, evaporate to dryness under reduced pressure with a rotary thin-film evaporation to remove the chloroform to form 2-methoxyestradiol and poloxamer Then add 20 g of olive oil filtered through a 0.22 μm microporous membrane, shake to disperse the solid dispersion, add 2.5% glycerin solution filtered through a 0.22 μm microporous membrane to 100 ml, stir to form colostrum, Then go through the micro-jet high-pressure milk homogenizer for three times, the operating pressure is 15k psi, the pH is adjusted to 5.5-8.0 with 0.1Mol/L hydrochloric acid or 0.1Mol/L sodium hydroxide, the 0.45μm microporous membrane is filtered, and the purified nitrogen flow protection Fill and seal, rotate the autoclave at 121°C, sterilize for 20 minutes, pour hot water and gradually cool to room temperature, ready to serve.

The product of this embodiment, the average particle diameter 290nm, Zeta potential-38mV is measured by the laser scattering particle measuring instrument; Negative; use red blood cell suspension to measure its hemolytic property, no red blood cell hemolysis and red blood cell aggregation phenomenon were seen in the test product within 3 hours; the release results in vitro are shown in Table 1, indicating that it has sustained release ability; the distribution results in mice are shown in Table 2, Demonstrated ability to target.

Example 3

Weigh 250 mg of 2-methoxyestradiol and 2.0 g of egg yolk lecithin, dissolve them in 5 ml of chloroform, evaporate to dryness under reduced pressure with a rotary thin-film evaporation to remove the chloroform to form a drug liquid crystal film, and then add in 0.22 μm microporous membrane filter 30g of soybean oil, shake to disperse the liquid crystal film, add the solution containing 0.5%% poloxamer and 5% sorbitol filtered through a 0.22μm microporous membrane to 100ml, stir to form colostrum, and then pass through the microjet The high-pressure milk homogenizer is milked three times, the operating pressure is 16k psi, the pH is adjusted to 5.5-8.0 with 0.1Mol/L hydrochloric acid or 0.1Mol/L sodium hydroxide, the 0.45μm microporous membrane is filtered, the nitrogen flow protection is filled and packaged, and the rotation Autoclave at 121°C, sterilize for 20 minutes, rinse with hot water and gradually cool to room temperature to get ready.

The product of this embodiment, the average particle diameter 190nm, Zeta potential-41mV is measured by the laser scattering particle measuring instrument; All were negative; the hemolyticity was measured with erythrocyte suspension, and no erythrocyte hemolysis and erythrocyte aggregation were seen in the test product within 3 hours; the in vitro release results are shown in Table 1, indicating that they have sustained release ability; the distribution results in mice are shown in Table 1 2, indicating the ability to target.

Example 4

Weigh 300 mg of 2-methoxyestradiol and 2.0 g of soybean hydrogenated phospholipids, dissolve them in 5 ml of chloroform, evaporate to dryness under reduced pressure with rotary thin-film evaporation, and remove the chloroform to form a drug liquid crystal film, and then add it through a 0.22 μm microporous filter membrane to filter Shake to disperse the liquid crystal film, add a solution containing 0.5% poloxamer and 2.5% glycerin filtered through a 0.22μm microporous membrane to 100ml, stir to form colostrum, and then pass through microjet high-pressure milk Homogenize milk three times, operating pressure 18k psi, use 0.1Mol/L hydrochloric acid or 0.1Mol/L sodium hydroxide to adjust the pH to 5.5-8.0, filter through a 0.45μm microporous membrane, purify the nitrogen flow to protect the filling package, and rotate the high pressure to extinguish Sterilize in a sterilizer at 121°C for 20 minutes, rinse with hot water and gradually cool to room temperature.

The product of this embodiment, the average particle diameter 180nm, Zeta potential-42mV is measured by the laser scattering particle measuring instrument; Negative; use red blood cell suspension to measure its hemolytic property, no red blood cell hemolysis and red blood cell aggregation phenomenon were seen in the test product within 3 hours; the release results in vitro are shown in Table 1, indicating that it has sustained release ability; the distribution results in mice are shown in Table 2, Demonstrated ability to target.

Above-mentioned embodiment list is as follows:

Table 1 each embodiment in vitro release result (%)

Table 2 The evaluation of distribution and targeting in mice of each embodiment

Example 5

Weigh 50 mg of 2-methoxyestradiol and 0.5 g of soybean hydrogenated phospholipids, dissolve them in 3 ml of chloroform, and evaporate to dryness under reduced pressure with a rotary thin-film evaporation to remove the chloroform to form a drug liquid crystal film, and then add in 0.22 μm microporous filter membrane to filter Shake to disperse the liquid crystal film, add the solution containing 2.5% glycerin filtered through a 0.22 μm microporous membrane to 100ml, stir to form colostrum, and then pass through the micro-jet high-pressure milk homogenizer for three times, and operate Pressure 17k psi, use 0.1Mol/L hydrochloric acid or 0.1Mol/L sodium hydroxide to adjust the pH to 5.5-8.0, filter through a 0.45μm microporous membrane, purify the nitrogen flow to protect the filling and packaging, rotate the autoclave at 121°C, and sterilize Bacteria for 20 minutes, pour hot water and gradually cool to room temperature, that is.

The average particle size is 290nm and the Zeta potential is -37mV as measured by a laser scattering particle analyzer; the product is stable at 4°C to 10°C; the systemic active allergic reaction is measured in guinea pigs, the intravenous low dose group is 2ml/kg, the high dose group is 6ml/kg, The test results were all negative; the hemolyticity of the red blood cell suspension was measured, and no red blood cell hemolysis and red blood cell aggregation were found in the test product within 3 hours.

Example 6

Weigh 500 mg of 2-methoxyestradiol and 5 g of soybean hydrogenated phospholipids, dissolve them in 10 ml of chloroform, evaporate to dryness under reduced pressure with rotary thin-film evaporation to remove the chloroform to form a drug liquid crystal film, and then add Soybean oil 50g, shake to disperse the liquid crystal film, add the solution containing 3% glucose filtered through a 0.22μm microporous membrane to 100ml, stir to form colostrum, and then go through the micro-jet high-pressure milk homogenizer three times, the operating pressure 17k psi, use 0.1Mol/L hydrochloric acid or 0.1Mol/L sodium hydroxide to adjust the pH to 5.5-8.0, filter through a 0.45μm microporous membrane, purify nitrogen flow, protect filling and packaging, and sterilize in a rotary autoclave at 121°C After 20 minutes, rinse with hot water and gradually cool to room temperature.

The average particle size is 260nm and the Zeta potential is -37mV as measured by a laser scattering particle analyzer; the product is stable at 4°C to 10°C, and the product has a high viscosity; the systemic active allergic reaction is measured in guinea pigs, and the intravenous low dose group is 1ml/kg, and the high The dose group was 3ml/kg, and the measurement results were all negative; the hemolyticity of the red blood cell suspension was measured, and no red blood cell hemolysis and red blood cell aggregation were seen in the test product within 3 hours.

Example 7

Weigh 50 mg of 2-methoxyestradiol and 0.5 g of soybean hydrogenated phospholipids, dissolve them in 3 ml of chloroform, and evaporate to dryness under reduced pressure with a rotary thin-film evaporation to remove the chloroform to form a drug liquid crystal film, and then add in 0.22 μm microporous filter membrane to filter Shake 5g of soybean oil to disperse the liquid crystal film, add a solution containing 0.1% poloxamer and 3% glycerin filtered through a 0.22μm microporous membrane to 100ml, stir to form colostrum, and then pass through microjet high-pressure milk Homogenize milk for three times, operating pressure 16k psi, use 0.1Mol/L hydrochloric acid or 0.1Mol/L sodium hydroxide to adjust the pH to 5.5-8.0, filter through a 0.45μm microporous membrane, purify the nitrogen flow to protect the filling package, and rotate the high pressure to extinguish Sterilize in a sterilizer at 121°C for 20 minutes, rinse with hot water and gradually cool to room temperature.

The average particle size is 220nm and the Zeta potential is -39mV measured by a laser scattering particle analyzer; the product is stable at 4°C to 10°C; the systemic active allergic reaction is measured in guinea pigs, and the intravenous low-dose group is 3ml/kg, and the high-dose group is 9ml/kg , The determination results were all negative; the hemolyticity was measured with red blood cell suspension, and no red blood cell hemolysis and red blood cell aggregation were found in the test product within 3 hours.

Example 8

Weigh 500 mg of 2-methoxyestradiol and 4.5 g of soybean hydrogenated phospholipids, dissolve them in 15 ml of chloroform, evaporate to dryness under reduced pressure with rotary thin-film evaporation, and remove the chloroform to form a drug liquid crystal film, and then add it to filter through a 0.22 μm microporous membrane Shake to disperse the liquid crystal film, add a solution containing 0.5% poloxamer and 3% sorbitol filtered through a 0.22μm microporous membrane to 100ml, stir to form colostrum, and then pass through the microjet high pressure Homogenize the milk for three times, operate at 17k psi, use 0.1Mol/L hydrochloric acid or 0.1Mol/L sodium hydroxide to adjust the pH to 5.5-8.0, filter with a 0.45μm microporous membrane, purify the nitrogen flow to protect the filling and packaging, and rotate under high pressure Sterilize in a sterilizer at 121°C for 20 minutes, rinse with hot water and gradually cool down to room temperature.

The average particle diameter is 205nm and the Zeta potential is -40mV as measured by a laser scattering particle analyzer; the product is stable at 4°C to 10°C; The dose group was 9ml/kg, and the results were all negative; the hemolyticity of the red blood cell suspension was measured, and no red blood cell hemolysis and red blood cell aggregation were seen in the test product within 3 hours.

In the systemic active allergy research of the composition of the present invention using guinea pigs, it is surprisingly found that the allergic reactions of the high and low dose groups are all negative. Among them, the dose of intravenous low dose group was 6mg/kg, and that of intravenous high dose group was 18mg/kg.

The composition of the present invention also obtains ideal results in the study of rabbit erythrocyte hemolysis reaction. According to the guiding principle of new drug research, the suspension of rabbit erythrocytes is taken, and the test product is diluted to 0.5 mg/ml of medicine with 0.9% normal saline for testing. No hemolysis and erythrocyte aggregation were observed within 3 hours.

The composition of the present invention uses 0.9% physiological saline as the release medium, the test product is placed in a dialysis bag, and the in vitro release study is carried out with the blue-turning method of the Chinese Pharmacopoeia. Temporal dose kinetics of methoxyestradiol treatment requirements.

The composition of the present invention uses small white mice to carry out distribution research in the body of tail vein administration, adopts the polyoxyethylene hydrogenated castor oil ethanol solution of 2-methoxyestradiol as contrast, uses relative uptake rate $r_e=\frac{{\left(\mathrm{AUCi}\right)}_P}{{\left({\mathrm{AUC}}_i\right)}_S}$ Evaluate its targeting rate ( _re represents the ratio of the area under the time curve of the sample target organ drug to the area under the control sample target organ drug time curve), and the results show that 2-methoxyestradiol is easily concentrated in the liver, spleen, and lung , kidney, breast, bone marrow and other organs.

Tests show that the present invention is a kind of nanoemulsion composition suitable for intravenous administration with slow-release ability and targeting ability in vivo, which can overcome the defects of oral preparations, is safe and reliable, and solves the 2- Methoxyestradiol 400mg high-dose medication technical problem, the present invention is an anti-cancer active ingredient, also includes the composition of the invention containing 2-methoxyestradiol for other medical purposes, 2-methoxyestradiol Oxyestradiol can also undergo a certain structural modification to obtain a new compound with similar physical and chemical properties to 2-methoxyestradiol. Its successful development is a great innovation in medicine and has huge social and economic benefits.

Claims (10)

1. 2-methoxy estradiol vena nano emulsions, it is characterized in that, 2-methoxyestradiol 0.05%～0.5% by w/v, oil for injection 5%～50%, emulsifying agent 0.05%～5%, isoosmotic adjusting agent 2%～6%, pH regulator agent and surplus are that water for injection is made, wherein get 2-methoxyestradiol 0.05%～0.5% earlier and emulsifying agent 0.05%～5% is used organic solvent dissolution, evaporated under reduced pressure eliminates organic solvent again, obtain the liquid crystal state or the solid dispersion of pharmaceutical emulsifier, add the oil for injection 5%～50% of 0.22 μ m filtering with microporous membrane or the aqueous mixture 5%～50% of 0.22 μ m filtering with microporous membrane again and disperse, stir and obtain colostrum; Pass through the high pressure dispersing emulsification machine again more than three times, operating pressure 5k～18k psi is 5.5～8.0 with pH regulator agent adjust pH, adds to the full amount of water for injection at last; Through 0.45 μ m filtering with microporous membrane, nitrogen purge gas stream protection filling encapsulation with 121 ℃ of rotation autoclaves, was sterilized 20 minutes, progressively was cooled to room temperature towards hot water again.

2. 2-methoxy estradiol vena nano emulsions according to claim 1 is characterized in that, said aqueous mixture is by emulsifying agent 0.05%～5%, the isoosmotic adjusting agent 2%～6% of w/v, and surplus is that water for injection mixes composition.

3. 2-methoxy estradiol vena nano emulsions according to claim 1, it is characterized in that, said oil for injection can be that soybean oil, olive oil, Oleum Sesami, safflower oil, Oleum Gossypii semen, safranine caul-fat, Semen Maydis oil, Oleum Fructus Bruceae, some medium chain wet goods can be the mixture of any in the acceptable oil of intravenous injection physiology or its two kinds, three kinds, and its content is preferably 15%～30% of compositions cumulative volume.

4. 2-methoxy estradiol vena nano emulsions according to claim 1 is characterized in that, said emulsifying agent can be phospholipid or poloxamer or the mixture of the two, and wherein phospholipid content in the compositions cumulative volume is preferably 0.5%～3%; Poloxamer content in the compositions cumulative volume is preferably 0.1%～1%; If emulsifying agent is the two mixture, the weight ratio of its phospholipid and poloxamer is 10: 1～1: 5, is preferably 5: 1～2: 1, and content is preferably 0.05%～5% of compositions cumulative volume.

5. 2-methoxy estradiol vena nano emulsions according to claim 4, it is characterized in that, said phospholipid is that soybean phospholipid, Ovum Gallus domesticus Flavus lecithin, Semen sojae atricolor hydrogenated phospholipid, hydrogenated yolk lecithin, two palmityl phospholipid, DSPE, Polyethylene Glycol-distearyl ethanolamine are any, also can be the phospholipid modified of list or polyclonal antibody, the phospholipid of phospholipid that galactosyl is modified, expressing polypeptide shed repair decorations any, or the mixture of two or more phospholipid of different nature.

6. 2-methoxy estradiol vena nano emulsions according to claim 4 is characterized in that, said poloxamer is any of poloxamer-188, poloxamer-338, poloxamer-407, and optimum is a poloxamer-188.

7. 2-methoxy estradiol vena nano emulsions according to claim 1 is characterized in that, said 2-methoxyestradiol optimum content is 0.1%～0.3% of a compositions cumulative volume.

8. 2-methoxy estradiol vena nano emulsions according to claim 1, it is characterized in that, said isoosmotic adjusting agent is any in glucose, sorbitol, glycerol and the kind can intravenous injection accepted by physiology, and in the compositions total volume percent: the consumption of glucose is 3%～5%, the consumption of sorbitol is 3%～6%, the glycerol consumption is 2%～3%.

9. 2-methoxy estradiol vena nano emulsions according to claim 1 is characterized in that, said pH regulator agent is hydrochloric acid or the sodium hydroxide that vein can be accepted by physiology.

10. 2-methoxy estradiol vena nano emulsions according to claim 1 is characterized in that, said organic solvent is chloroform or acetone.