Fulvestrant pharmaceutical composition for injection and preparation method thereof

Abstract

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

Technical Field

[0001] The present invention relates to the technical field of injection preparation, and in particular to a fulvestrant pharmaceutical composition for injection and a preparation method thereof. Background Art

[0002] Fulvestrant is a new type of steroidal estrogen receptor antagonist. Different from tamoxifen and aromatase inhibitors, Fulvestrant is a new type of estrogen receptor antagonist with a novel mechanism of action. It can exert anti-tumor effects by blocking and degrading ER and reducing the expression level of ER.

[0003] The existing fulvestrant drug is mainly used for treatment in the form of injection. The commonly used fulvestrant injection was developed by AstraZeneca Pharmaceuticals Co., Ltd. and approved for marketing in the United States in 2002, in Europe in 2004 and in my country in 2010. The trade name is Fusodexa, which is approved for use in postmenopausal estrogen receptor-positive locally advanced or metastatic breast cancer that recurs after or during adjuvant anti-estrogen therapy, or progresses during anti-estrogen therapy.

[0004] In order to improve the solubility and stability of fulvestrant, the existing fulvestrant injection mostly uses solvents such as benzyl benzoate and ethanol. However, the use of such solvents is likely to increase drug irritation, thereby leading to side effects of drug treatment. If the addition of such drugs is reduced, the stability of fulvestrant injection is likely to decrease. Therefore, how to ensure the stability of fulvestrant injection while using less solvent is an important research direction at this stage. Summary of the invention

[0005] In view of the shortcomings of the prior art, the present invention provides a fulvestrant pharmaceutical composition for injection and a preparation method thereof, which ensures the drug stability of fulvestrant injection in the absence of an organic solvent and improves the safety of the drug.

[0006] To achieve the above objectives, the technical solution of the present invention is implemented through the following technical solutions:

[0007] A fulvestrant pharmaceutical composition for injection, which is composed of the following substances in percentage by mass: 5%-10% of fulvestrant, 0.1%-0.16% of a first surfactant, 4%-6% of castor oil for injection, 1%-3% of glycerol for injection, 1%-1.4% of oleic acid, 0.6%-0.8% of phospholipids, 0.3%-0.6% of a second surfactant, and the rest is water for injection.

[0008] Preferably, the first surfactant is poloxamer 188.

[0009] Preferably, the second surfactant is a mixture of soybean lecithin and isopropyl myristate in a mass ratio of 2:1.

[0010] The preparation method of the fulvestrant pharmaceutical composition for injection comprises the following steps:

[0011] S1, mixing fulvestrant and the first surfactant, adding the mixture to a solvent, stirring and dissolving the mixture uniformly at 0.4-0.8 Mpa, and obtaining a first mixed solution for standby use;

[0012] S2, adding castor oil for injection, glycerol for injection and oleic acid to the first mixed solution, subjecting the mixture to ultrasonic vibration treatment and then centrifugation, and then rotary evaporation to remove the solvent to obtain a composite material for standby use;

[0013] S3, adding the second surfactant and phospholipid into the water for injection, stirring and mixing evenly to obtain a second mixed solution for standby use;

[0014] S4, adding 1 / 3-1 / 5 of the second mixed solution to the composite material, stirring and mixing evenly, to obtain a third mixed solution for standby use;

[0015] S5. Place the third mixed liquid in a high-pressure reactor at 0.8-1.2 Mpa, and drop the remaining second mixed liquid into the third mixed liquid under ice-water bath conditions, and stir at a speed of 1200-1600 r / min while dropping. After the dropping is completed, adjust the pressure to 4-6 Mpa, 8-10 Mpa, and 0.6-0.8 Mpa in sequence, let it stand for treatment, and then fill it to obtain a Fulvestrant pharmaceutical composition for injection.

[0016] Preferably, the solvent in step S1 is a mixture of benzyl alcohol, diethylene glycol ethyl ether and ethanol in a mass ratio of 3:2:1, and the solid-liquid ratio of fulvestrant to the solvent is 1:3-5.

[0017] Preferably, in step S2, the power of ultrasonic oscillation is 400-600 W, the time of ultrasonic oscillation is 15-20 min, and the speed of centrifugation is 3200-4000 r / min, and the time of centrifugation is 5-10 min.

[0018] Preferably, the method of stirring and mixing uniformly in step S3 is to stir and mix at a speed of 200-400 r / min for 20-30 min at a water bath temperature of 45-55°C.

[0019] Preferably, the stirring and mixing in step S4 is carried out at a speed of 600-800 r / min for 20-40 min.

[0020] Preferably, the dripping rate in step S5 is 80-100 drops / min.

[0021] Preferably, the specific method of the static treatment in step S5 is to sequentially statically treat at a pressure of 4-6 MPa for 40-60 min, statically treat at a pressure of 8-10 MPa for 15-30 min, and statically treat at a pressure of 0.6-0.8 MPa for 20-40 min, and keep an ice water bath during the entire static process.

[0022] The present invention provides a fulvestrant pharmaceutical composition for injection and a preparation method thereof, which has the advantages over the prior art in that:

[0023] The fulvestrant pharmaceutical composition for injection of the present invention does not contain any organic solvent, thus ensuring the safety of the injection. In the preparation process, fulvestrant is dissolved in a solvent, mixed with an oil agent, subjected to ultrasonic treatment and centrifugation, and then the solvent is evaporated to form a microemulsion. A surfactant, phospholipid and water are then mixed and added dropwise and pressure-changed to form a stable solution, thereby effectively improving the storage stability of the injection. DETAILED DESCRIPTION

[0024] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention is clearly and completely described below in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0025] Embodiment 1:

[0026] The following solvent is prepared by mixing benzyl alcohol, diethylene glycol ethyl ether and ethanol in a mass ratio of 3:2:1; 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.

[0027] Preparation of Fulvestrant pharmaceutical composition for injection:

[0028] (1) mixing fulvestrant and a first surfactant and adding the mixture to a solvent, wherein the solid-liquid ratio of fulvestrant to the solvent is controlled to be 1:4, and stirring and dissolving the mixture uniformly at 0.6 MPa to obtain a first mixed solution for standby use;

[0029] (2) Castor oil for injection, glycerol for injection and oleic acid are mixed and added to the first mixed solution, and ultrasonically shaken for 15 minutes at a power of 600 W, and then centrifuged at a speed of 3500 r / min for 8 minutes, and then rotary evaporated to remove the solvent to obtain a composite material for use;

[0030] (3) adding the second surfactant and phospholipid to water for injection, stirring at a speed of 300 r / min at a water bath temperature of 50° C. for 25 min to obtain a second mixed solution for use;

[0031] (4) adding 1 / 4 of the second mixed solution to the composite material, stirring at a speed of 800 r / min for 30 min, and obtaining a third mixed solution for standby use;

[0032] (5) placing the third mixed solution in a 1 MPa autoclave, and dripping the remaining second mixed solution into the third mixed solution at a dripping speed of 100 drops / min under an ice-water bath condition, and stirring at a speed of 1400 r / min while dripping. After the dripping is completed, standing for 50 min at a pressure of 5 MPa, standing for 20 min at a pressure of 9 MPa, and standing for 30 min at a pressure of 0.6 MPa, and keeping an ice-water bath during the entire standing process, and then filling to obtain a Fulvestrant pharmaceutical composition for injection.

[0033] The fulvestrant pharmaceutical compositions for injection of experimental groups 1-4 were prepared according to the above preparation method, and the content of each component in each group is shown in Table 1 below:

[0034] Table 1

[0035]

[0036] Comparative Example 1:

[0037] Referring to the raw material ratio of Experimental Group 1 in Example 1 above, the following method was used to prepare the Fulvestrant pharmaceutical composition for injection:

[0038] (1) mixing fulvestrant and a first surfactant and adding the mixture to a solvent, wherein the solid-liquid ratio of fulvestrant to the solvent is controlled to be 1:4, and stirring and dissolving the mixture uniformly at 0.6 MPa to obtain a first mixed solution for standby use;

[0039] (2) Castor oil for injection, glycerol for injection and oleic acid are mixed and added to the first mixed solution, and ultrasonically shaken for 15 minutes at a power of 600 W, and then centrifuged at a speed of 3500 r / min for 8 minutes, and then rotary evaporated to remove the solvent to obtain a composite material for use;

[0040] (3) adding the second surfactant and phospholipid to water for injection, stirring at a speed of 300 r / min at a water bath temperature of 50° C. for 25 min to obtain a second mixed solution for use;

[0041] (4) adding 1 / 4 of the second mixed solution to the composite material, stirring at a speed of 800 r / min for 30 min, and obtaining a third mixed solution for standby use;

[0042] (5) The remaining second mixed solution was added dropwise to the third mixed solution at a dropping speed of 100 drops / min, and stirred at a speed of 1400 r / min. After the addition was completed, the mixture was allowed to stand for 2 h and then filled to obtain a fulvestrant pharmaceutical composition for injection.

[0043] Comparative Example 2:

[0044] Referring to the raw material ratio of Experimental Group 1 in Example 1 above, the following method was used to prepare the Fulvestrant pharmaceutical composition for injection:

[0045] (1) mixing fulvestrant and a first surfactant and adding the mixture to a solvent, wherein the solid-liquid ratio of fulvestrant to the solvent is controlled to be 1:4, and stirring and dissolving the mixture uniformly at 0.6 MPa to obtain a first mixed solution for standby use;

[0046] (2) Castor oil for injection, glycerol for injection and oleic acid are mixed and added to the first mixed solution, and ultrasonically shaken for 15 minutes at a power of 600 W, and then centrifuged at a speed of 3500 r / min for 8 minutes, and then rotary evaporated to remove the solvent to obtain a composite material for use;

[0047] (3) adding the second surfactant and phospholipid to water for injection, stirring at a speed of 300 r / min at a water bath temperature of 50° C. for 25 min to obtain a second mixed solution for use;

[0048] (4) adding the second mixed solution to the composite material, stirring at a speed of 1400 r / min for 30 min, and then standing under an ice-water bath condition at a pressure of 5 MPa for 50 min, at a pressure of 9 MPa for 20 min, and at a pressure of 0.6 MPa for 30 min, and keeping the ice-water bath during the entire standing process, and then filling to obtain a fulvestrant pharmaceutical composition for injection.

[0049] Comparative Example 3:

[0050] Referring to the raw material ratio of Experimental Group 1 in Example 1 above, the following method was used to prepare the Fulvestrant pharmaceutical composition for injection:

[0051] (1) mixing fulvestrant and a first surfactant and adding the mixture to a solvent, wherein the solid-liquid ratio of fulvestrant to the solvent is controlled to be 1:4, and stirring and dissolving the mixture uniformly at 0.6 MPa to obtain a first mixed solution for standby use;

[0052] (2) Castor oil for injection, glycerol for injection and oleic acid are mixed and added to the first mixed solution, and ultrasonically shaken for 15 minutes at a power of 600 W, and then centrifuged at a speed of 3500 r / min for 8 minutes, and then rotary evaporated to remove the solvent to obtain a composite material for use;

[0053] (3) adding the second surfactant and phospholipid to water for injection, stirring at a speed of 300 r / min at a water bath temperature of 50° C. for 25 min to obtain a second mixed solution for use;

[0054] (4) The second mixed solution was added to the composite material, stirred at a speed of 1400 r / min for 30 min, allowed to stand for 2 h, and then filled to obtain a fulvestrant pharmaceutical composition for injection.

[0055] Detection:

[0056] 1. Testing the stability of the fulvestrant pharmaceutical compositions for injection prepared in the above experimental groups 1-4 and comparative examples 1-3:

[0057] 1. Freeze-thaw stability test:

[0058] Each group of Fulvestrant pharmaceutical compositions for injection was filled into a transparent vial, placed in a freezer at -18°C for 2 hours, taken out and thawed in a 25°C water bath, and then restored to room temperature to complete one freeze-thaw cycle. The properties of the injection solution and the changes in the Fulvestrant content of each group of Fulvestrant pharmaceutical compositions for injection after 0, 5, and 15 freeze-thaw cycles were detected (the content data of Fulvestrant detected after 0 days of placement was set as 100%, and the relative contents before and after were calculated). The specific results are shown in Table 2 below:

[0059] Table 2

[0060]

[0061] 2. High temperature stability test:

[0062] Each group of Fulvestrant pharmaceutical compositions for injection was filled into transparent vials, and then placed in a stabilization box, the storage temperature was controlled at 60°C, and the mixture was placed for 0 days, 20 days, and 50 days. The properties of each group of Fulvestrant pharmaceutical compositions for injection and the changes in the content of Fulvestrant were detected after placement. The specific results are shown in Table 3 below:

[0063] Table 3

[0064]

[0065]

[0066] As shown in Tables 2 and 3 above, the fulvestrant pharmaceutical composition for injection prepared in Experimental Group 1 has high stability.

[0067] 2. Drug irritation test:

[0068] Subcutaneous injection of rabbits was used to detect the irritation of each group of fulvestrant pharmaceutical compositions for injection. The hair on both sides of the back of the rabbits was shaved, and then 1 ml of the above fulvestrant pharmaceutical composition for injection was subcutaneously injected on the left side, and an equal amount of normal saline was injected on the right side. The skin changes at the injection site were observed at 20 minutes and 1 hour after the injection to observe whether erythema and edema occurred. The specific results are shown in Table 4 below:

[0069] Table 4

[0070] Group Injection 20min Injection 1h Experimental Group 1 No erythema, no edema No erythema, no edema Experimental Group 2 No erythema, no edema Minor erythema, no edema Experimental Group 3 No erythema, no edema Minor erythema, no edema Experimental Group 4 No erythema, no edema Minor erythema, no edema Comparative Example 1 No erythema, no edema No erythema, no edema Comparative Example 2 No erythema, no edema No erythema, no edema Comparative Example 3 No erythema, no edema No erythema, no edema

[0071] As can be seen from the above table, the fulvestrant pharmaceutical composition for injection prepared by the experimental group 1 and the control groups 1-3 has low irritation, and based on the above stability test, the fulvestrant pharmaceutical composition for injection prepared by the experimental group 1 has a better and superior effect.

[0072] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A pharmaceutical composition of fulvestrant for injection, characterized in that: The fulvestrant injection pharmaceutical composition is composed of the following substances in percentage by mass: 5%-10% fulvestrant, 0.1%-0.16% of a first surfactant, 4%-6% of castor oil for injection, 1%-3% of glycerol for injection, 1%-1.4% of oleic acid, 0.6%-0.8% of phospholipids, 0.3%-0.6% of a second surfactant, and the rest is water for injection; The preparation method of the fulvestrant pharmaceutical composition for injection comprises the following steps: S1, mixing fulvestrant and the first surfactant, adding the mixture to a solvent, stirring and dissolving the mixture uniformly at 0.4-0.8 Mpa, and obtaining a first mixed solution for standby use; S2, adding castor oil for injection, glycerol for injection and oleic acid to the first mixed solution, subjecting the mixture to ultrasonic vibration treatment and then centrifugation, and then rotary evaporation to remove the solvent to obtain a composite material for standby use; S3, adding the second surfactant and phospholipid into the water for injection, stirring and mixing evenly to obtain a second mixed solution for standby use; S4, adding 1 / 3-1 / 5 of the second mixed solution to the composite material, stirring and mixing evenly, to obtain a third mixed solution for standby use; S5. Place the third mixed liquid in a high-pressure reactor at 0.8-1.2 Mpa, and drop the remaining second mixed liquid into the third mixed liquid under ice-water bath conditions, and stir at a speed of 1200-1600 r / min while dropping. After the dropping is completed, adjust the pressure to 4-6 Mpa, 8-10 Mpa, and 0.6-0.8 Mpa in sequence, let it stand for treatment, and then fill it to obtain a Fulvestrant pharmaceutical composition for injection.

2. A pharmaceutical composition for injection of fulvestrant according to claim 1, characterized in that: The first surfactant is poloxamer 188.

3. A fulvestrant pharmaceutical composition for injection according to claim 1, characterized in that: The second surfactant is a mixture of soybean lecithin and isopropyl myristate in a mass ratio of 2:

1.

4. A fulvestrant pharmaceutical composition for injection according to claim 1, characterized in that: In the step S1, the solvent is a mixture of benzyl alcohol, diethylene glycol ethyl ether and ethanol in a mass ratio of 3:2:1, and the solid-liquid ratio of fulvestrant to the solvent is 1:3-5.

5. A fulvestrant pharmaceutical composition for injection according to claim 1, characterized in that: In step S2, the power of ultrasonic oscillation is 400-600W, the time of ultrasonic oscillation is 15-20min, and the speed of centrifugation is 3200-4000r / min, and the time of centrifugation is 5-10min.

6. A fulvestrant pharmaceutical composition for injection according to claim 1, characterized in that: The method of stirring and mixing uniformly in step S3 is to stir and mix at a speed of 200-400 r / min for 20-30 min at a water bath temperature of 45-55° C.

7. A fulvestrant pharmaceutical composition for injection according to claim 1, characterized in that: The stirring and mixing in step S4 is carried out at a speed of 600-800 r / min for 20-40 min.

8. A fulvestrant pharmaceutical composition for injection according to claim 1, characterized in that: The dripping rate in step S5 is 80-100 drops / min.

9. A fulvestrant pharmaceutical composition for injection according to claim 1, characterized in that: The specific method of the static treatment in step S5 is to sequentially statically treat the sample at a pressure of 4-6 MPa for 40-60 min, at a pressure of 8-10 MPa for 15-30 min, and at a pressure of 0.6-0.8 MPa for 20-40 min, and keep an ice water bath during the entire static process.

Images