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CN118717660B - Fulvestrant pharmaceutical composition for injection and preparation method thereof - Google Patents

Fulvestrant pharmaceutical composition for injection and preparation method thereof Download PDF

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CN118717660B
CN118717660B CN202410750393.1A CN202410750393A CN118717660B CN 118717660 B CN118717660 B CN 118717660B CN 202410750393 A CN202410750393 A CN 202410750393A CN 118717660 B CN118717660 B CN 118717660B
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injection
fulvestrant
pharmaceutical composition
mixed solution
surfactant
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CN118717660A (en
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熊忠辉
陈磊
丁新书
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Huzhou Arthur Pharmaceutical Co ltd
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Huzhou Arthur Pharmaceutical Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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Abstract

本发明提供一种注射用氟维司群药物组合物及其制备方法，涉及注射液制备技术领域。所述注射用氟维司群药物组合物由氟维司群、第一表面活性剂、注射用蓖麻油、注射用甘油、油酸、磷脂、第二表面活性剂和注射用水组成，且制备方式为先将氟维司群混合第一表面活性剂溶于溶剂后与注射用蓖麻油、注射用甘油、油酸震荡离心后除去溶剂，再混合第二表面活性剂和注射用水进行变压处理。本发明克服了现有技术的不足，在无有机溶剂的情况下保证氟维司群注射液的药物稳定性，同时提升药物的安全性。The present invention provides a fulvestrant pharmaceutical composition for injection and a preparation method thereof, and relates to the technical field of injection preparation. The fulvestrant pharmaceutical composition for injection is composed of fulvestrant, a first surfactant, castor oil for injection, glycerol for injection, oleic acid, phospholipids, a second surfactant and water for injection, and the preparation method is to first mix fulvestrant with the first surfactant and dissolve it in a solvent, then shake and centrifuge it with castor oil for injection, glycerol for injection, and oleic acid, and then remove the solvent, and then mix the second surfactant and water for injection for pressure change treatment. The present invention overcomes the shortcomings of the prior art, ensures the drug stability of fulvestrant injection in the absence of an organic solvent, and improves the safety of the drug.

Description

Fulvestrant pharmaceutical composition for injection and preparation method thereof
Technical Field
The invention relates to the technical field of injection preparation, in particular to a fulvestrant pharmaceutical composition for injection and a preparation method thereof.
Background
Fulvestrant is a novel steroid estrogen receptor antagonist, and fulvestrant is different from tamoxifen and an aromatase inhibitor and has a novel action mechanism, and can play an anti-tumor role by blocking and degrading ER and reducing the expression level of ER.
The prior fulvestrant drug is mainly used in the form of injection, the conventionally used fulvestrant injection is developed by the company of America pharmaceutical Co, and is approved to be marketed in the United states in 2002, europe in 2004 and China in 2010 respectively, and the product is named Fushide, and the approval can be used for recurrent postmenopausal estrogen receptor positive locally advanced or metastatic breast cancer after or during auxiliary antiestrogen treatment or progressing in antiestrogen treatment.
In the prior art, solvents such as benzyl benzoate, ethanol and the like are mostly adopted in order to improve the solubility and stability of fulvestrant, but the use of the solvents is easy to cause the increase of drug irritation, thereby causing side effects of drug treatment, and if the addition of the drugs is reduced, the stability of fulvestrant injection is easy to be reduced, so how to ensure the stability of fulvestrant injection while using fewer solvents is an important research direction at present.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides the fulvestrant pharmaceutical composition for injection and the preparation method thereof, which ensure the pharmaceutical stability of fulvestrant injection under the condition of no organic solvent and improve the safety of the medicine.
In order to achieve the above object, the technical scheme of the present invention is realized by the following technical scheme:
The fulvestrant pharmaceutical composition for injection comprises, by mass, 5% -10% of fulvestrant, 0.1% -0.16% of a first surfactant, 4% -6% of castor oil for injection, 1% -3% of glycerin for injection, 1% -1.4% of oleic acid, 0.6% -0.8% of phospholipid, 0.3% -0.6% of a second surfactant and the balance of water for injection.
Preferably, the first surfactant is poloxamer 188.
Preferably, the second surfactant is a mixture of soybean phospholipid and isopropyl myristate in a mass ratio of 2:1.
The preparation method of the fulvestrant pharmaceutical composition for injection comprises the following steps:
S1, mixing fulvestrant and a first surfactant, adding the mixture into a solvent, and stirring and dissolving uniformly under 0.4-0.8Mpa to obtain a first mixed solution for later use;
S2, mixing the castor oil for injection, the glycerol for injection and the oleic acid, adding the mixture into the first mixed solution, carrying out ultrasonic vibration treatment, centrifuging, and removing the solvent by rotary evaporation to obtain a composite material for later use;
S3, mixing the second surfactant and the phospholipid into the water for injection, and uniformly stirring and mixing to obtain a second mixed solution for later use;
s4, adding 1/3-1/5 of the second mixed solution into the composite material, and stirring and uniformly mixing to obtain a third mixed solution for later use;
S5, placing the third mixed solution in a high-pressure reaction kettle of 0.8-1.2Mpa, dropwise adding the rest second mixed solution into the third mixed solution under the ice water bath condition, stirring at the rotating speed of 1200-1600r/min while dropwise adding, sequentially adjusting the pressure to the range of 4-6Mpa, 8-10Mpa and 0.6-0.8Mpa after dropwise adding is completed, standing for treatment, and then filling to obtain the fulvestrant pharmaceutical composition for injection.
Preferably, in the step S1, the solvent is obtained by mixing benzyl alcohol, diethylene glycol diethyl ether and ethanol in a mass ratio of 3:2:1, and the feed liquid ratio of fulvestrant to the solvent is 1:3-5.
Preferably, in the step S2, the power of the ultrasonic vibration is 400-600W, the time of the ultrasonic vibration is 15-20min, the rotation speed of the centrifugation is 3200-4000r/min, and the time of the centrifugation is 5-10min.
Preferably, in the step S3, the stirring and mixing are performed for 20-30min at the water bath temperature of 45-55 ℃ and the rotating speed of 200-400 r/min.
Preferably, the stirring and mixing in the step S4 is performed at a rotation speed of 600-800r/min for 20-40min.
Preferably, the dropping rate in the step S5 is 80-100 drops/min.
Preferably, the specific manner of the standing treatment in the step S5 is that the standing treatment is performed for 40-60min under the pressure of 4-6Mpa, the standing treatment is performed for 15-30min under the pressure of 8-10Mpa, the standing treatment is performed for 20-40min under the pressure of 0.6-0.8Mpa, and the ice water bath is kept in the whole standing process.
The invention provides a fulvestrant pharmaceutical composition for injection and a preparation method thereof, and has the advantages compared with the prior art that:
The fulvestrant pharmaceutical composition for injection has no addition of organic solvent, ensures the use safety of injection, and in the preparation process, fulvestrant is dissolved in the solvent, mixed with oil solution for ultrasonic treatment and centrifugation, then the solvent is evaporated to prepare microemulsion, and then the surfactant, phospholipid and water are mixed dropwise and subjected to pressure transformation to prepare stable solution, so that the storage stability of the injection is effectively improved.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions in the embodiments of the present invention will be clearly and completely described in the following in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1:
the composition is prepared by mixing benzyl alcohol, diethylene glycol diethyl ether and ethanol in a mass ratio of 3:2:1, wherein the first surfactant is poloxamer 188, and the second surfactant is a mixture of soybean lecithin and isopropyl myristate in a mass ratio of 2:1.
Preparation of fulvestrant pharmaceutical composition for injection:
(1) Mixing fulvestrant and a first surfactant, adding the mixture into a solvent, controlling the feed liquid ratio of fulvestrant to the solvent to be 1:4, and uniformly stirring and dissolving the mixture under 0.6Mpa to obtain a first mixed solution for later use;
(2) Mixing and adding castor oil for injection, glycerol for injection and oleic acid into the first mixed solution, performing ultrasonic oscillation treatment for 15min by adopting 600W power, centrifuging for 8min by adopting a rotating speed of 3500r/min, and removing the solvent by rotary evaporation to obtain a composite material for later use;
(3) Mixing a second surfactant and phospholipid into water for injection, and stirring at a water bath temperature of 50 ℃ at a rotating speed of 300r/min for 25min to obtain a second mixed solution for later use;
(4) Adding 1/4 of the second mixed solution into the composite material, and stirring at a rotating speed of 800r/min for 30min to obtain a third mixed solution for later use;
(5) Placing the third mixed solution into a high-pressure reaction kettle of 1Mpa, dropwise adding the rest second mixed solution into the third mixed solution at a dropwise speed of 100 drops/min under the condition of ice water bath, stirring at a rotating speed of 1400r/min while dropwise adding, sequentially standing for 50min under a pressure of 5Mpa after dropwise adding is completed, standing for 20min under a pressure of 9Mpa, standing for 30min under a pressure of 0.6Mpa, keeping an ice water bath in the whole standing process, and then filling to obtain the fulvestrant pharmaceutical composition for injection.
The fulvestrant pharmaceutical compositions for injection of experimental groups 1-4 were formulated according to the above preparation method, and the contents of the components in each group are shown in table 1 below:
TABLE 1
Comparative example 1:
Referring to the raw material ratios of experimental group 1 in the above example 1, fulvestrant pharmaceutical compositions for injection were prepared by the following method:
(1) Mixing fulvestrant and a first surfactant, adding the mixture into a solvent, controlling the feed liquid ratio of fulvestrant to the solvent to be 1:4, and uniformly stirring and dissolving the mixture under 0.6Mpa to obtain a first mixed solution for later use;
(2) Mixing and adding castor oil for injection, glycerol for injection and oleic acid into the first mixed solution, performing ultrasonic oscillation treatment for 15min by adopting 600W power, centrifuging for 8min by adopting a rotating speed of 3500r/min, and removing the solvent by rotary evaporation to obtain a composite material for later use;
(3) Mixing a second surfactant and phospholipid into water for injection, and stirring at a water bath temperature of 50 ℃ at a rotating speed of 300r/min for 25min to obtain a second mixed solution for later use;
(4) Adding 1/4 of the second mixed solution into the composite material, and stirring at a rotating speed of 800r/min for 30min to obtain a third mixed solution for later use;
(5) And (3) dripping the rest second mixed solution into the third mixed solution at a dripping speed of 100 drops/min, stirring at a rotating speed of 1400r/min while dripping, standing for 2h after dripping is completed, and filling to obtain the fulvestrant pharmaceutical composition for injection.
Comparative example 2:
Referring to the raw material ratios of experimental group 1 in the above example 1, fulvestrant pharmaceutical compositions for injection were prepared by the following method:
(1) Mixing fulvestrant and a first surfactant, adding the mixture into a solvent, controlling the feed liquid ratio of fulvestrant to the solvent to be 1:4, and uniformly stirring and dissolving the mixture under 0.6Mpa to obtain a first mixed solution for later use;
(2) Mixing and adding castor oil for injection, glycerol for injection and oleic acid into the first mixed solution, performing ultrasonic oscillation treatment for 15min by adopting 600W power, centrifuging for 8min by adopting a rotating speed of 3500r/min, and removing the solvent by rotary evaporation to obtain a composite material for later use;
(3) Mixing a second surfactant and phospholipid into water for injection, and stirring at a water bath temperature of 50 ℃ at a rotating speed of 300r/min for 25min to obtain a second mixed solution for later use;
(4) Adding the second mixed solution into the composite material, stirring at 1400r/min for 30min, sequentially standing for 50min under 5Mpa pressure in ice water bath, standing for 20min under 9Mpa pressure, standing for 30min under 0.6Mpa pressure, maintaining ice water bath during the whole standing process, and filling to obtain fulvestrant pharmaceutical composition for injection.
Comparative example 3:
Referring to the raw material ratios of experimental group 1 in the above example 1, fulvestrant pharmaceutical compositions for injection were prepared by the following method:
(1) Mixing fulvestrant and a first surfactant, adding the mixture into a solvent, controlling the feed liquid ratio of fulvestrant to the solvent to be 1:4, and uniformly stirring and dissolving the mixture under 0.6Mpa to obtain a first mixed solution for later use;
(2) Mixing and adding castor oil for injection, glycerol for injection and oleic acid into the first mixed solution, performing ultrasonic oscillation treatment for 15min by adopting 600W power, centrifuging for 8min by adopting a rotating speed of 3500r/min, and removing the solvent by rotary evaporation to obtain a composite material for later use;
(3) Mixing a second surfactant and phospholipid into water for injection, and stirring at a water bath temperature of 50 ℃ at a rotating speed of 300r/min for 25min to obtain a second mixed solution for later use;
(4) Adding the second mixed solution into the composite material, stirring at 1400r/min for 30min, standing for 2h, and packaging to obtain fulvestrant pharmaceutical composition for injection.
And (3) detection:
1. stability of fulvestrant pharmaceutical compositions for injection prepared in the above experimental groups 1 to 4 and comparative examples 1 to 3 were examined:
1. And (3) detecting freeze thawing stability:
Filling each group of fulvestrant pharmaceutical compositions for injection into a transparent penicillin bottle, placing the fulvestrant pharmaceutical compositions for injection at a temperature of 18 ℃ below zero for 2 hours, taking out the fulvestrant pharmaceutical compositions for injection, melting the fulvestrant pharmaceutical compositions in a water bath at 25 ℃ and recovering the fulvestrant pharmaceutical compositions to normal temperature, finishing one freeze thawing, detecting the properties of injection and the content change of fulvestrant of each group of fulvestrant pharmaceutical compositions for injection after 0 times, 5 times and 15 times of freeze thawing (the content data detected by 0d of fulvestrant placement is set as 100 percent, calculating the relative content before and after), and the specific results are shown in the following table 2:
TABLE 2
2. High temperature stability detection:
Filling each group of fulvestrant pharmaceutical compositions for injection into a transparent penicillin bottle, placing the transparent penicillin bottle in a stabilizing box, controlling the preservation temperature at 60 ℃, placing the fulvestrant pharmaceutical compositions for injection for 0d, 20d and 50d, and detecting the properties and the content change of fulvestrant after the fulvestrant pharmaceutical compositions for injection are placed, wherein the specific results are shown in the following table 3:
TABLE 3 Table 3
As can be seen from tables 2 and 3, the fulvestrant pharmaceutical composition for injection prepared in experimental group 1 has higher stability.
2. Drug irritation detection:
The irritation of each group of fulvestrant pharmaceutical compositions for injection was detected by subcutaneous injection in rabbits, shaving was performed on both sides of the backs of the rabbits, 1ml of the fulvestrant pharmaceutical composition for injection was injected subcutaneously on the left side, an equal amount of physiological saline was injected subcutaneously on the right side, skin changes at the injection site were observed at the time of injection for 20min and 1h, and whether erythema and edema were caused or not was observed, and specific results are shown in the following table 4:
TABLE 4 Table 4
Group of Injection for 20min Injection for 1h
Experiment group 1 No erythema and no edema No erythema and no edema
Experiment group 2 No erythema and no edema Small amount of erythema and no edema
Experiment group 3 No erythema and no edema Small amount of erythema and no edema
Experiment group 4 No erythema and no edema Small amount of erythema and no edema
Comparative example 1 No erythema and no edema No erythema and no edema
Comparative example 2 No erythema and no edema No erythema and no edema
Comparative example 3 No erythema and no edema No erythema and no edema
From the above table, the fulvestrant pharmaceutical composition for injection prepared in the experimental group 1 and the control groups 1-3 has lower irritation, and the fulvestrant pharmaceutical composition for injection prepared in the experimental group 1 has better and superior effects by combining the stability detection.
The foregoing embodiments are merely for illustrating the technical solution of the present invention, but not for limiting the same, and although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those skilled in the art that modifications may be made to the technical solution described in the foregoing embodiments or equivalents may be substituted for parts of the technical features thereof, and that such modifications or substitutions do not depart from the spirit and scope of the technical solution of the embodiments of the present invention in essence.

Claims (9)

1. The fulvestrant pharmaceutical composition for injection is characterized by comprising, by mass, 5% -10% of fulvestrant, 0.1% -0.16% of a first surfactant, 4% -6% of castor oil for injection, 1% -3% of glycerin for injection, 1% -1.4% of oleic acid, 0.6% -0.8% of phospholipid, 0.3% -0.6% of a second surfactant and the balance of water for injection;
The preparation method of the fulvestrant pharmaceutical composition for injection comprises the following steps:
S1, mixing fulvestrant and a first surfactant, adding the mixture into a solvent, and stirring and dissolving uniformly under 0.4-0.8Mpa to obtain a first mixed solution for later use;
S2, mixing the castor oil for injection, the glycerol for injection and the oleic acid, adding the mixture into the first mixed solution, carrying out ultrasonic vibration treatment, centrifuging, and removing the solvent by rotary evaporation to obtain a composite material for later use;
S3, mixing the second surfactant and the phospholipid into the water for injection, and uniformly stirring and mixing to obtain a second mixed solution for later use;
s4, adding 1/3-1/5 of the second mixed solution into the composite material, and stirring and uniformly mixing to obtain a third mixed solution for later use;
S5, placing the third mixed solution in a high-pressure reaction kettle of 0.8-1.2Mpa, dropwise adding the rest second mixed solution into the third mixed solution under the ice water bath condition, stirring at the rotating speed of 1200-1600r/min while dropwise adding, sequentially adjusting the pressure to the range of 4-6Mpa, 8-10Mpa and 0.6-0.8Mpa after dropwise adding is completed, standing for treatment, and then filling to obtain the fulvestrant pharmaceutical composition for injection.
2. The fulvestrant pharmaceutical composition for injection according to claim 1, wherein said first surfactant is poloxamer 188.
3. The fulvestrant pharmaceutical composition for injection according to claim 1, wherein said second surfactant is a mixture of soybean phospholipid and isopropyl myristate in a mass ratio of 2:1.
4. The fulvestrant pharmaceutical composition for injection according to claim 1, wherein the solvent in the step S1 is obtained by mixing benzyl alcohol, diethylene glycol diethyl ether and ethanol in a mass ratio of 3:2:1, and the feed liquid ratio of fulvestrant to solvent is 1:3-5.
5. The fulvestrant pharmaceutical composition for injection according to claim 1, wherein the power of ultrasonic vibration in the step S2 is 400-600W, the time of ultrasonic vibration is 15-20min, the rotational speed of centrifugation is 3200-4000r/min, and the time of centrifugation is 5-10min.
6. The fulvestrant pharmaceutical composition for injection according to claim 1, wherein the stirring and mixing in the step S3 is performed for 20-30min at a water bath temperature of 45-55 ℃ and a rotational speed of 200-400 r/min.
7. The fulvestrant pharmaceutical composition for injection according to claim 1, wherein the stirring and mixing mode in the step S4 is stirring treatment at a rotation speed of 600-800r/min for 20-40min.
8. The fulvestrant pharmaceutical composition for injection according to claim 1, wherein the dripping rate in step S5 is 80-100 drops/min.
9. The fulvestrant pharmaceutical composition for injection according to claim 1, wherein the specific manner of the standing treatment in the step S5 is that the fulvestrant pharmaceutical composition is sequentially subjected to standing under the pressure of 4-6Mpa for 40-60min, the fulvestrant pharmaceutical composition is subjected to standing under the pressure of 8-10Mpa for 15-30min, the fulvestrant pharmaceutical composition is subjected to standing under the pressure of 0.6-0.8Mpa for 20-40min, and an ice water bath is maintained in the whole standing process.
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CN107362142A (en) * 2016-05-13 2017-11-21 山东新时代药业有限公司 A kind of fulvestrant lipidosome injection and preparation method thereof

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