Mitartan freeze-dried preparation and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a mitortan freeze-dried preparation and a preparation method thereof. The preparation method comprises the following steps: dissolving mitartan in ethanol to obtain a mitartan ethanol stock solution, preparing a mixed solution containing the mitartan ethanol stock solution, normal saline, a serum solution and amino acid, and freeze-drying the mixed solution to obtain the mitartan freeze-dried preparation. The serum solution comprises one of human serum, bovine serum and a serum albumin solution. According to the dosage form obtained by the method, the water solubility of the mitartan can be remarkably improved; the stabilizing time of the redissolved solution can be effectively prolonged by adding the amino acid; the method is simple to operate, mild in condition and suitable for large-scale production, and solves the key problem of poor water solubility of mitoctan; the mitortan freeze-dried preparation is good in water solubility and can be well absorbed by a human body, so that mitortan has a good drug effect.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a mitotane freeze-dried preparation and a preparation method thereof. Background Art

[0002] Adrenocortical carcinoma (ACC) is a malignant tumor originating from the adrenal cortex. It has a low incidence rate, but is characterized by high malignancy, rapid disease progression, and easy local metastasis. Surgical resection is the preferred treatment method, but for patients with advanced disease or systemic recurrence who cannot undergo surgical treatment, drug therapy and other methods are required.

[0003] Currently, Mitotane is the only orphan drug approved for the treatment of ACC. Mitotane is not only suitable for ACC patients who are inoperable or have extensive metastases, but can also prolong the recurrence-free survival and overall survival of ACC patients who undergo surgical treatment.

[0004] Monitoring the blood concentration of mitotane is a key step in the drug administration process, because the effective therapeutic concentration window of mitotane is extremely narrow. The recommended concentration in the expert consensus on mitotane treatment of adrenocortical carcinoma (2021) is 14-20 mg / L. Below this concentration, the optimal therapeutic effect cannot be achieved. In order to achieve an effective blood concentration, the recommended starting dose is 2-6 g of mitotane per day, divided into 3-4 doses. After 2-3 weeks of treatment, the blood concentration of mitotane should be monitored, and then the dosage should be adjusted according to the blood concentration to achieve the therapeutic blood concentration.

[0005] However, mitotane has very poor water solubility, only 0.1 mg / L. The current commercial dosage form is a 500 mg tablet. Even at a dose of up to 6 g / day (i.e., 12 tablets per day), more than 50% of patients are unable to achieve a therapeutic blood concentration of 14 mg / L due to its poor water solubility and low bioavailability. Summary of the invention

[0006] The technical problem to be solved by the present invention is to provide a mitotane freeze-dried preparation and a preparation method thereof, so as to solve the problem of low solubility of mitotane in water.

[0007] The technical solution of the present invention to solve the above technical problems is as follows:

[0008] The invention provides a preparation method of a mitotane freeze-dried preparation. The method comprises the following steps: mixing mitotane with ethanol to obtain a mitotane ethanol solution, preparing a mixed solution containing the mitotane ethanol stock solution, physiological saline, a serum solution and amino acids, and freeze-drying the mixed solution to obtain the mitotane freeze-dried preparation; the serum solution comprises one of human serum, bovine serum and serum albumin solution.

[0009] Based on the above technical solution, the present invention can also be improved as follows.

[0010] Furthermore, the mass volume ratio of the mitotane to the ethanol is 5-50 mg:1 mL.

[0011] Furthermore, the serum solution is a serum albumin solution, and the concentration of the serum albumin solution is 40 to 55 g / L.

[0012] Furthermore, the amino acid is one of aspartic acid, glutamic acid, cysteine ​​and arginine.

[0013] Furthermore, in the mixed solution, the mass ratio of mitotane, the physiological saline, serum albumin and amino acids is 1:1000:100-125:2-5.

[0014] Furthermore, the method further comprises the following steps: adding the serum-like solution and the amino acid into physiological saline, stirring evenly until the amino acid is completely dissolved, adding the mitotane ethanol solution, stirring evenly, and obtaining the mixed solution.

[0015] Furthermore, the freeze-drying temperature is -10°C to -50°C.

[0016] The present invention also provides a mitotane freeze-dried preparation, which is prepared by the above method.

[0017] The present invention also provides a method for reconstitution of a mitotane freeze-dried preparation, comprising mixing the mitotane freeze-dried preparation with physiological saline, wherein every 50 mg of the mitotane freeze-dried preparation is mixed with at least 100 μl of physiological saline for reconstitution.

[0018] The present invention also provides a solution containing mitotane, which is obtained by adopting the above-mentioned re-dissolution method.

[0019] The present invention also provides a pharmaceutical composition for treating cancer, comprising the above-mentioned mitotane freeze-dried preparation, and also comprising a pharmaceutically acceptable inorganic substance and a carrier.

[0020] The beneficial effects of the present invention are:

[0021] (1) The preparation method of the mitotane freeze-dried preparation of the present invention adopts ethanol to dissolve mitotane, and then volatilizes the ethanol during the freeze-drying process, which can significantly improve the solubility of mitotane;

[0022] (2) In the preparation method of the mitotane freeze-dried preparation of the present invention, the addition of amino acids can effectively prolong the stability time of the solution after reconstitution;

[0023] (3) The preparation method of the mitotane freeze-dried preparation of the present invention has simple steps, mild conditions, low cost, and has a very significant effect on improving the solubility of mitotane, which can enable mitotane to be more widely used;

[0024] (4) The mitotane freeze-dried preparation of the present invention has good water solubility, so that the mitotane therein has good bioavailability and can quickly reach the desired concentration when used;

[0025] (5) The mitotane freeze-dried preparation of the present invention has a relatively long stability time, which can ensure that mitotane has sufficient time to exert its drug effect. DETAILED DESCRIPTION

[0026] The principles and features of the present invention are described below. The examples given are only used to explain the present invention and are not used to limit the scope of the present invention.

[0027] The preparation method of the mitotane freeze-dried preparation of the present invention comprises the following steps: mixing mitotane with ethanol to obtain a mitotane ethanol solution, preparing a mixed solution containing a mitotane ethanol stock solution, physiological saline, a serum solution and amino acids, and finally freeze-drying the mixed solution to obtain the mitotane freeze-dried preparation; the serum solution comprises one of human serum, bovine serum and serum albumin solution.

[0028] The preparation method of the mitotane freeze-dried preparation of the present invention adopts ethanol to dissolve mitotane, and then volatilizes the ethanol during the freeze-drying process, so that the solubility of mitotane can be significantly improved, so that the obtained freeze-dried powder can be well re-dissolved and has a long stability time after re-dissolution.

[0029] In the preparation method of the present invention, ethanol volatilizes in the subsequent freeze-drying process, and therefore, the amount of ethanol used is such that it can dissolve mitotane.

[0030] Preferably, in the preparation method of the present invention, the mass volume ratio of mitotane to ethanol is 5-50 mg:1 ml.

[0031] Preferably, the serum solution is a serum albumin solution, and the concentration of the serum albumin solution is 40-55 g / L.

[0032] It should be noted that serum albumin can be human serum albumin or bovine serum albumin. Human serum albumin is natural human serum albumin obtained from human plasma pools, or it can be recombinant human serum albumin. Bovine serum albumin is commercially available natural bovine serum albumin, or it can be recombinant bovine serum albumin. The serum albumin used in the present invention is serum albumin that does not contain fatty acids.

[0033] Taking into account subsequent applications, human serum albumin is preferably used in the method of the present invention.

[0034] Physiological saline refers to a sodium chloride solution commonly used in physiological experiments or clinical practice, whose osmotic pressure is basically equal to the osmotic pressure of animal or human plasma.

[0035] Preferably, the amino acid may be one of aspartic acid, glutamic acid, cysteine ​​and arginine.

[0036] More preferably, aspartic acid can effectively prolong the stability time of the reconstituted solution.

[0037] Aspartic acid is specifically L-aspartic acid, which can also be called L(+)aminosuccinic acid; L(+)-aminosuccinic acid; L(+)-aminosuccinic acid; L(+)-aspartic acid; L(+)-aspartic acid; L(+)-aspartic acid; L-aspartic acid; L-aspartic acid. The chemical formula is as follows:

[0038]

[0039] Aspartic acid available in the market is white crystal or crystalline powder, with a slightly sour taste. It is soluble in boiling water, slightly soluble in water (0.5%) at 25°C, easily soluble in dilute acid and sodium hydroxide solution, insoluble in ethanol and ether, and decomposes when heated to 270°C. Its isoelectric point is 2.77, and its specific rotation is related to the solvent in which it is dissolved. It is right-handed in acid solution, left-handed in alkaline solution, and right-handed in aqueous solution.

[0040] In the mixed solution, the mass ratio of mitotane, normal saline and serum albumin is 1:1000-2000:100-125.

[0041] Specifically, in some embodiments, the mass ratio of mitotane, saline, and serum albumin is 1:1000:100, in some embodiments, the mass ratio of mitotane, saline, and serum albumin is 1:1200:100, in some embodiments, the mass ratio of mitotane, saline, and serum albumin is 1:1400:100, in some embodiments, the mass ratio of mitotane, saline, and serum albumin is 1:1600:100, in some embodiments, the mass ratio of mitotane, saline, and serum albumin is 1:1800:100. The mass ratio of serum albumin is 1:1800:100. In some embodiments, the mass ratio of mitotane, saline and serum albumin is 1:2000:100. In some embodiments, the mass ratio of mitotane, saline and serum albumin is 1:1000:110. In some embodiments, the mass ratio of mitotane, saline and serum albumin is 1:1000:120. In some embodiments, the mass ratio of mitotane, saline and serum albumin is 1:1000:125, etc.

[0042] Specifically, in some embodiments, the mass ratio of mitotane to aspartic acid is 1:2, in some embodiments, the mass ratio of mitotane to aspartic acid is 1:2.5, in some embodiments, the mass ratio of mitotane to aspartic acid is 1:3, in some embodiments, the mass ratio of mitotane to aspartic acid is 1:3.5, in some embodiments, the mass ratio of mitotane to aspartic acid is 1:4, in some embodiments, the mass ratio of mitotane to aspartic acid is 1:4.5, in some embodiments, the mass ratio of mitotane to aspartic acid is 1:5, etc.

[0043] Preferably, in the mixed solution, the mass ratio of mitotane, normal saline, serum albumin and aspartic acid is 1:1000-2000:100-125:2-5.

[0044] Specifically, in some embodiments, the mass ratio of mitotane, saline, serum albumin and aspartic acid is 1:1000:100:2, in some embodiments, the mass ratio of mitotane, saline, serum albumin and aspartic acid is 1:1100:110:2.1, in some embodiments, the mass ratio of mitotane, saline, serum albumin and aspartic acid is 1:1200:120:2.2, in some embodiments, the mass ratio of mitotane, saline, serum albumin and aspartic acid is 1:1200:125: 2.5, in some embodiments, the mass ratio of mitotane, saline, serum albumin and aspartic acid is 1:1300:105:3, in some embodiments, the mass ratio of mitotane, saline, serum albumin and aspartic acid is 1:1500:115:3.5, in some embodiments, the mass ratio of mitotane, saline, serum albumin and aspartic acid is 1:1800:120:4, in some embodiments, the mass ratio of mitotane, saline, serum albumin and aspartic acid is 1:2000:125:5, etc.

[0045] The freeze-drying method used in the present invention is a conventional freeze-drying method, and the freeze-drying temperature is -20°C to -80°C.

[0046] The mitotane freeze-dried preparation of the present invention is prepared by the above method; the freeze-dried preparation comprises mitotane, serum-like substances and amino acids, and also comprises pharmaceutically acceptable inorganic substances. The freeze-dried preparation has good solubility, greatly increases the solubility of mitotane, and has the advantage of high stability.

[0047] Pharmaceutically acceptable inorganic substances include elements such as Na and Cl brought by physiological saline, and may also include other pharmaceutical carriers such as sugars, esters, etc.

[0048] However, ethanol is absent or almost absent in the lyophilized preparation.

[0049] The method for reconstituting the mitotane freeze-dried preparation of the present invention comprises mixing the above-mentioned mitotane freeze-dried preparation with physiological saline, wherein each 50 mg of the mitotane freeze-dried preparation is mixed with at least 100 μl of physiological saline for reconstituting.

[0050] In the reconstituted solution obtained by the above method, the concentration of mitotane can reach 0.286-0.33 mg / ml, and the solubility of mitotane in physiological water is about 0.01 mg / 2.5 L (1 mg / 250 L), that is, 4×10 -6 mg / ml, it can be seen that the solubility of mitotane in the reconstituted solution has been significantly improved.

[0051] The solution containing mitotane of the present invention is obtained by adopting the above-mentioned reconstitution method.

[0052] The pharmaceutical composition for treating cancer of the present invention comprises the above-mentioned mitotane freeze-dried preparation or the above-mentioned solution containing mitotane.

[0053] Specifically, the cancer is adrenocortical carcinoma.

[0054] The present invention is described below by means of specific examples.

[0055] Example 1

[0056] In this embodiment, the lyophilized preparation of mitotane is prepared by the method of the present invention and reconstituted, and the specific steps are as follows:

[0057] (1) Prepare 10 mg / ml mitotane ethanol stock solution: Place 20 mg of mitotane in a 2 ml EP tube, add 2 ml ethanol, and shake well for later use.

[0058] (2) Prepare 50 g / L human / bovine serum albumin solution: Take 1.25 g human serum albumin, add 25 ml saline to dissolve, shake well and set aside.

[0059] (3) Prepare bovine serum or human serum: dissolve the bovine serum or human serum in a 37°C water bath and take 20 ml of the bovine serum or human serum for later use;

[0060] (4) Preparation of a composition solution of mitotane, human / bovine serum albumin and amino acids: 10 ml of normal saline was placed in a beaker, 25 ml of human bovine serum albumin solution (50 g / L) and 30 mg of aspartic acid were added, and the mixture was stirred evenly until the aspartic acid was dissolved. 1 ml of mitotane ethanol stock solution was added, and the mixture was stirred evenly to obtain a composition of a yellow clear liquid, in which the concentration of mitotane was 0.286 mg / ml.

[0061] (5) Preparation of a composition solution of mitotane, bovine serum or human serum: Take 20 ml of physiological saline in a beaker, add 18.25 ml of bovine serum or human serum solution, stir evenly, add 1 ml of mitotane ethanol stock solution, stir evenly to obtain a light yellow clear liquid composition, in which the concentration of mitotane is 0.26 mg / ml.

[0062] (6) Freeze-drying: The compositions obtained in step (4) and step (5) were respectively packaged in 10 ml glass bottles, and freeze-dried at -40°C to obtain freeze-dried powders, which were then separately packaged in 50 ml centrifuge tubes.

[0063] (7) Reconstitution: Take 0.3432 g of the freeze-dried powder and add 10 ml of normal saline to reconstitute it. The concentration of mitotane in the obtained reconstituted solution is 0.286 mg / mL.

[0064] Example 2 Mixed solution and lyophilized powder prepared using bovine serum

[0065] (1) Preparation of 10 mg / ml mitotane ethanol solution: Place 20 mg of mitotane in a 2 ml EP tube, add 2 ml of ethanol, and shake well for later use.

[0066] (2) Comparison of the solubility of mitotane ethanol solution in bovine serum and physiological saline: In 10 ml of physiological saline, the above mitotane ethanol solution was added gradually until 1.2 mg was added, and a white precipitate was observed in the solution with the naked eye; while in 10 ml of bovine serum solution, the above mitotane ethanol solution was added gradually until 12 mg was added, and a white precipitate was observed in the solution. Therefore, the solubilization effect of bovine serum on mitotane ethanol solution is 10 times that of physiological saline.

[0067] (3) Preparation of a composite solution of mitotane ethanol solution and bovine serum: The optimal concentration of mitotane in physiological saline and bovine serum solution is 0.26 mg / ml, and the solution clarity is optimal at this concentration. At this time, the mass ratio of mitotane, physiological saline and bovine serum is 1:2000:1755. At this optimal mass ratio, the optimal amounts of mitotane ethanol solution, physiological saline and bovine serum are: 4 mg, 8 ml and 7.3 ml, as shown in Table 1:

[0068] Table 1

[0069] Mitotane ethanol solution Normal saline Bovine serum 4mg 8ml 7.3ml

[0070] (4) Freeze-drying: The composition obtained in step (3) was divided into 10 ml glass bottles and freeze-dried at -40°C to obtain freeze-dried powder, which was divided into 50 ml centrifuge tubes.

[0071] (5) Reconstitution: The freeze-dried powder prepared with the above optimal ratio is reconstituted to the optimal concentration of 0.26 mg / ml. The room temperature stability can be improved to 24 to 48 hours, and the clarity is also greatly improved.

[0072] (6) Comparison of the solubility of untreated mitotane powder and the lyophilized powder prepared by the method of this embodiment in physiological saline: The lyophilized powder prepared by the above optimal ratio, containing 4 mg of mitotane, can be reconstituted with at least 2 ml of physiological saline, and the solubility is 2 mg / ml, which is 500,000 times higher than the solubility of mitotane in pure physiological saline (0.004 mg / L).

[0073] Example 3 Mixed solution and lyophilized powder prepared using human serum

[0074] Considering the subsequent application issues, this example uses human serum instead of bovine serum for the experiment.

[0075] (1) Preparation of 10 mg / mL mitotane ethanol solution: Take 20 mg of mitotane in a 2 ml EP tube, add 2 ml of ethanol, shake well and set aside.

[0076] (2) Comparison of the solubility of mitotane ethanol solution in human serum and physiological saline: In 10 ml of physiological saline, the above mitotane ethanol solution was added gradually until 1.2 mg was added, and a white precipitate was observed in the solution with the naked eye; while in 10 ml of human serum solution, the above mitotane ethanol solution was added gradually until 12 mg was added, and then a white precipitate was observed in the solution. Therefore, the solubilization effect of human serum on mitotane ethanol solution is consistent with that of bovine serum, and is also 10 times that of physiological saline.

[0077] (3) Preparation of a composite solution of mitotane ethanol solution and human serum: The optimal concentration of mitotane in physiological saline and human serum solution is also 0.26 mg / ml, and the solution clarity is optimal at this concentration. At this time, the mass ratio of mitotane, physiological saline and human serum is 1:2000:1755. At this optimal mass ratio, the optimal amounts of mitotane ethanol solution, physiological saline and human serum are: 4 mg, 8 ml and 7.3 ml, as shown in Table 2:

[0078] Table 2

[0079] Mitotane ethanol solution Normal saline human serum 4mg 8ml 7.3ml

[0080] (4) Freeze-drying: The composition obtained in step (3) was divided into 10 ml glass bottles and freeze-dried at -40°C to obtain freeze-dried powder, which was divided into 50 ml centrifuge tubes.

[0081] (5) Reconstitution: When the freeze-dried powder prepared with the above optimal ratio is reconstituted to 0.033 mg / ml, the solution is clearest and stable for the longest time, at which time the stability time is 6 days.

[0082] (6) Comparison of the maximum reconstitution concentrations of the lyophilized powders prepared using bovine serum and human serum: 50 mg of the mitotane bovine serum lyophilized powder prepared in Example 2 can be reconstituted with at least 200 μl of saline, and its maximum reconstitution concentration is 250 mg / ml; while 50 mg of the mitotane human serum lyophilized powder prepared in this example can be reconstituted with at least 100 μl of saline, and its maximum reconstitution concentration is 500 mg / ml. Therefore, compared with bovine serum, the lyophilized powder prepared using human serum has higher reconstitution properties.

[0083] Example 4 Mixture prepared using human / bovine serum albumin solution and lyophilized powder

[0084] Although bovine serum and human serum can significantly improve the solubility of mitotane, in practical applications, serum has problems such as large batch-to-batch variation and high potential safety hazards. Serum albumin has high cost-effectiveness, small batch-to-batch variation, and better safety. Therefore, this example uses human serum albumin solution and bovine serum albumin solution respectively to investigate their effects on the solubility of mitotane.

[0085] (1) Preparation of 10 mg / mL mitotane ethanol solution: Take 20 mg of mitotane in a 2 ml EP tube, add 2 ml of ethanol, shake well and set aside.

[0086] (2) Prepare 50 g / L human serum albumin solution and bovine serum albumin solution: Dissolve 1.25 g human serum albumin and 1.25 g bovine serum albumin in 25 ml saline solution respectively, shake well and set aside.

[0087] (3) Comparison of the solubility of mitotane ethanol solution in human / bovine serum albumin solution (50 g / L) and normal saline: In 10 ml of normal saline, the above mitotane ethanol solution was added gradually until 1.2 mg was added, and a white precipitate was observed in the solution with the naked eye; while in 10 ml of human / bovine serum albumin solution (50 g / L), the above mitotane ethanol solution was added gradually until 8.04 mg was added, and a white precipitate was observed in the solution. Therefore, the solubilization effect of 50 g / L human / bovine serum albumin solution on mitotane ethanol solution is 6.7 times that of normal saline.

[0088] (4) Preparation of a composite solution of mitotane ethanol solution and human / bovine serum albumin solution (50 g / L): The optimal concentration of mitotane in physiological saline and human / bovine serum albumin solution (50 g / L) is 0.286 mg / ml, and the solution clarity is optimal at this concentration. At this time, the mass ratio of mitotane, physiological saline and human / bovine serum albumin solution (50 g / L) is 1:1000:125. At this optimal mass ratio, the optimal dosage of mitotane ethanol solution, physiological saline and human / bovine serum albumin solution (50 g / L) is: 1 mg, 1 ml, 2.5 ml, as shown in Table 3:

[0089] Table 3

[0090] Mitotane ethanol solution Normal saline Human / bovine serum albumin solution (50g / L) 1mg 1ml 2.5ml

[0091] (5) Freeze-drying: The composition obtained in step (4) was divided into 10 ml glass bottles and freeze-dried at -40°C to obtain freeze-dried powder, which was divided into 50 ml centrifuge tubes.

[0092] (6) Reconstitution: Take 0.3432 g of the lyophilized powder and add 10 ml of physiological saline to reconstitute it. The concentration of mitotane in the reconstituted solution is 0.286 mg / mL. The lyophilized powder prepared by the above optimal ratio has the longest stability time of 7 days when reconstituted to 0.286 mg / ml.

[0093] Example 5 Mixture and lyophilized powder prepared using human / bovine serum albumin solution and amino acids

[0094] In order to better simulate serum, this example investigates the effect of adding amino acids on the solubility of mitotane based on the use of human / bovine serum albumin solution. This example uses aspartic acid as an example.

[0095] (1) Preparation of 10 mg / mL mitotane ethanol solution: Take 20 mg of mitotane in a 2 ml EP tube, add 2 ml of ethanol, shake well and set aside.

[0096] (2) Prepare 50 g / L human serum albumin solution and bovine serum albumin solution: Dissolve 1.25 g human serum albumin and 1.25 g bovine serum albumin in 25 ml saline solution respectively, shake well and set aside.

[0097] (3) Preparation of a composite solution of mitotane ethanol solution, human / bovine serum albumin solution (50 g / L) and aspartic acid: The optimal concentration of mitotane in physiological saline, human / bovine serum albumin solution (50 g / L) and aspartic acid is 0.286 mg / ml, at which the solution has the best clarity.

[0098] At this time, the mass ratio of mitotane, saline, human / bovine serum albumin, and aspartic acid is 1:1000:125:2. At this optimal mass ratio, the optimal dosages of mitotane ethanol solution, saline, human / bovine serum albumin solution (50 g / L), and aspartic acid are: 1 mg, 1 ml, 2.5 ml, and 3 mg, as shown in Table 4:

[0099] Table 4

[0100] Mitotane ethanol solution Normal saline Human / bovine serum albumin solution (50g / L) Aspartic acid 1mg 1ml 2.5ml 3mg

[0101] (4) Freeze-drying: The composition obtained in step (4) was divided into 10 ml glass bottles and freeze-dried at -40°C to obtain freeze-dried powder, which was divided into 50 ml centrifuge tubes.

[0102] (5) Reconstitution: Take 0.3432 g of freeze-dried powder and add 10 ml of normal saline to reconstitute. The concentration of mitotane in the reconstituted solution is 0.286 mg / mL. The freeze-dried powder prepared by the above optimal ratio has the longest stability time of 21 days when reconstituted to 0.286 mg / ml.

[0103] The above experimental results show that when no amino acids are added, the freeze-dried powder prepared by using human / bovine serum albumin at the optimal ratio and optimal dosage is stable for 7 days when reconstituted to 0.286 mg / ml. After adding a certain amount of aspartic acid, when reconstituted to the above concentration, the stable time is 21 days, indicating that the solubility and stability of the mitotane solution are further improved after mixing human / bovine serum albumin with amino acids.

[0104] In the description of the present invention, it should be noted that the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0105] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing a mitotane freeze-dried preparation, characterized in that: Mitotane is dissolved in ethanol to obtain a mitotane ethanol stock solution, a mixed solution containing the mitotane ethanol stock solution, physiological saline, a serum solution and amino acids is prepared, and the mixed solution is freeze-dried to obtain the mitotane freeze-dried preparation; the serum solution includes one of human serum, bovine serum and serum albumin solution.

2. The method for preparing a lyophilized preparation of mitotane according to claim 1, characterized in that: The mass volume ratio of the mitotane to the ethanol is 5-50 mg:1 mL.

3. The method for preparing a lyophilized preparation of mitotane according to claim 1, characterized in that: The serum solution is a serum albumin solution, and the concentration of the serum albumin solution is 40-55 g / L.

4. The method for preparing a lyophilized preparation of mitotane according to claim 3, characterized in that: The amino acid is one of aspartic acid, glutamic acid, cysteine, arginine, lysine and glycine.

5. The method for preparing a lyophilized preparation of mitotane according to claim 4, characterized in that: In the mixed solution, the mass ratio of mitotane, the physiological saline, serum albumin and amino acids is 1:1000-4000:100-150:2-8.

6. The method for preparing a lyophilized preparation of mitotane according to any one of claims 1 to 5, characterized in that: The following steps are also included: The serum-like solution and the amino acid are added to the physiological saline, and the mixture is stirred evenly until the amino acid is completely dissolved. The mitotane ethanol stock solution is added and stirred evenly to obtain the mixed solution.

7. A mitotane freeze-dried preparation, characterized in that: The method is prepared by the method according to any one of claims 1 to 6.

8. A method for reconstitution of a mitotane freeze-dried preparation, characterized in that: The mitotane freeze-dried preparation according to claim 7 is mixed with physiological saline, wherein every 50 mg of the mitotane freeze-dried preparation is mixed with at least 100 μl of physiological saline for reconstitution.

9. A solution containing mitotane, characterized in that The method is adopted as claimed in claim 8.

10. A pharmaceutical composition for treating cancer, characterized in that: The invention comprises the solution containing mitotane as claimed in claim 9, and further comprises a pharmaceutically acceptable inorganic substance and a carrier.

Images