Mitotane lyophilized formulation and preparation method therefor

Abstract

The present invention relates to the technical field of pharmaceutical formulations, and in particular, to a mitotane lyophilized formulation and a preparation method therefor. Mitotane is dissolved in ethanol to obtain a mitotane ethanol stock solution; a mixed solution containing the mitotane ethanol stock solution, normal saline, a serum-like solution, and an amino acid is prepared; the mixed solution is lyophilized to obtain the mitotane lyophilized formulation. The serum-like solution comprises one of human serum, bovine serum, and serum albumin solutions. The dosage form obtained by the method can significantly improve the water solubility of mitotane. The addition of the amino acid can effectively prolong the stabilization time of the reconstituted solution. The method features simple operations and mild conditions, is suitable for large-scale production, and solves the critical problem of poor water solubility of mitotane. The mitotane lyophilized formulation has good water solubility and can be well absorbed by the human body, such that mitotane exhibits good pharmaceutical efficacy.

Description

A lyophilized mitotane formulation and its preparation method Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and more specifically, to a mitotane lyophilized formulation and its preparation method. Background Technology

[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. However, for patients who are not eligible for surgery due to advanced stage or systemic recurrence, drug therapy and other methods are required.

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

[0004] Monitoring mitotane blood concentrations is a critical step in the dosing process because mitotane has an extremely narrow effective therapeutic window. The recommended concentration in the expert consensus on mitotane for the treatment of adrenocortical carcinoma (2021) is 14–20 mg / L; concentrations below this range will not achieve optimal therapeutic effects. To achieve effective blood concentrations, the recommended starting dose is 2–6 g of mitotane daily, divided into 3–4 doses. Monitoring of mitotane blood concentrations should begin after 2–3 weeks of treatment, and the dosage should be adjusted accordingly to achieve therapeutic blood concentrations.

[0005] However, mitotane has very poor water solubility, at only 0.1 mg / L. Currently, the commercially available dosage form is 500 mg tablets. Even at a dose as high as 6 g / day (i.e., 12 tablets per day), more than 50% of patients still cannot achieve a therapeutic blood concentration of 14 mg / L due to its poor water solubility and low bioavailability.

[0006] Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a mitotane lyophilized formulation and preparation method to solve the problem of low solubility of mitotane in water.

[0008] The technical solution of the present invention to solve the above-mentioned technical problems is as follows:

[0009] This invention provides a method for preparing a mitotane lyophilized formulation, comprising mixing mitotane with ethanol to obtain a mitotane ethanol solution, preparing a mixture containing the mitotane ethanol stock solution, physiological saline, serum solution and amino acids, and lyophilizing the mixture to obtain the mitotane lyophilized formulation; wherein the serum solution includes one of human serum, bovine serum and serum albumin solution.

[0010] Based on the above technical solution, the present invention can be further improved as follows.

[0011] Furthermore, the mass-to-volume ratio of mitotane to ethanol is 5–50 mg: 1 mL.

[0012] Furthermore, the serum solution is a serum albumin solution with a concentration of 40–55 g / L.

[0013] Furthermore, the amino acid is one of aspartic acid, glutamic acid, cysteine, and arginine.

[0014] Furthermore, in the mixture, the mass ratio of mitotane, the saline, serum albumin, and amino acids is 1:1000:100-125:2-5.

[0015] Furthermore, the method includes the following steps: adding the serum solution and the amino acid to physiological saline, stirring until the amino acid is completely dissolved, adding the mitotane ethanol solution, stirring until homogeneous, and obtaining the mixture.

[0016] Furthermore, the freeze-drying temperature is -10℃ to -50℃.

[0017] The present invention also provides a mitotane lyophilized formulation, which is prepared by the method described above.

[0018] The present invention also provides a method for reconstitution of a mitotane lyophilized preparation, wherein the above-mentioned mitotane lyophilized preparation is mixed with physiological saline, wherein each 50 mg of the mitotane lyophilized preparation is mixed with at least 100 μl of physiological saline for reconstitution.

[0019] The present invention also provides a solution containing mitotane, obtained by the reconstitution method described above.

[0020] The present invention also provides a pharmaceutical composition for treating cancer, comprising the lyophilized mitotane formulation as described above, and further comprising pharmaceutically acceptable inorganic substances and a carrier.

[0021] The beneficial effects of this invention are as follows:

[0022] (1) The method for preparing the mitotane lyophilized formulation of the present invention uses ethanol to dissolve mitotane and then allows the ethanol to evaporate during the lyophilization process, which can significantly improve the solubility of mitotane.

[0023] (2) In the preparation method of the mitotane lyophilized formulation of the present invention, the addition of amino acids can effectively prolong the stability time of the solution after reconstitution;

[0024] (3) The method for preparing the mitotane lyophilized formulation of the present invention is simple, mild, and low in cost, and has a very significant effect on improving the solubility of mitotane, which can enable mitotane to be used more widely.

[0025] (4) The mitotane lyophilized formulation of the present invention has good water solubility, which makes the mitotane therein have good bioavailability and can quickly reach the required concentration when used.

[0026] (5) The mitotane lyophilized formulation of the present invention has a long stability time, which can ensure that mitotane has enough time to exert its drug effect. Detailed Implementation

[0027] The principles and features of the present invention are described below. The examples given are only for explaining the present invention and are not intended to limit the scope of the present invention.

[0028] The method for preparing the mitotane lyophilized formulation of the present invention involves mixing mitotane with ethanol to obtain a mitotane ethanol solution, preparing a mixture containing mitotane ethanol stock solution, physiological saline, serum solution and amino acids, and finally lyophilizing the mixture to obtain the mitotane lyophilized formulation; the serum solution includes one of human serum, bovine serum and serum albumin solution.

[0029] The method for preparing the mitotane lyophilized formulation of the present invention involves dissolving mitotane in ethanol and then evaporating the ethanol during the lyophilization process. This significantly improves the solubility of mitotane, allowing the resulting lyophilized powder to be well reconstituted and to have a longer stability time after reconstitution.

[0030] In the preparation method of the present invention, ethanol evaporates during the subsequent freeze-drying process. Therefore, the standard for the amount of ethanol used is that it is sufficient to dissolve mitotane.

[0031] Preferably, in the preparation method of the present invention, the mass-to-volume ratio of mitotane to ethanol is 5-50 mg: 1 ml.

[0032] Preferably, the serum solution is a serum albumin solution with a concentration of 40–55 g / L.

[0033] 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 banks, 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 this invention is fatty acid-free serum albumin.

[0034] Considering subsequent applications, human serum albumin is preferably used in the method of this invention.

[0035] Physiological saline refers to a sodium chloride solution with an osmotic pressure that is basically equal to that of animal or human blood plasma, commonly used in physiological experiments or clinical practice.

[0036] Preferably, the amino acid can be one of aspartic acid, glutamic acid, cysteine, or arginine.

[0037] Furthermore, aspartic acid can effectively prolong the stability time of the reconstituted solution.

[0038] Aspartic acid is specifically L-aspartic acid, and 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. Its chemical formula is shown below:

[0039] Commercially available aspartic acid is a white crystalline powder or crystalline crystalline substance with a slightly acidic taste. It is soluble in boiling water, slightly soluble in water (0.5%) at 25°C, readily soluble in dilute acids and sodium hydroxide solution, insoluble in ethanol and ether, and decomposes upon heating to 270°C. Its isoelectric point is 2.77, and its specific rotation depends on the solvent. It is dextrorotatory in acidic solutions, levorotatory in alkaline solutions, and dextrorotatory in aqueous solutions.

[0040] In the mixture, the mass ratio of mitotane, physiological 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 is 1:1200:100; in some embodiments, the mass ratio is 1:1400:100; in some embodiments, the mass ratio is 1:1600:100; and in some embodiments, the mass ratio is 1:1600:100. 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; and in some embodiments, the mass ratio of mitotane to aspartic acid is 1:5, etc.

[0043] Preferably, the mass ratio of mitotane, physiological saline, serum albumin and aspartic acid in the mixture 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 other embodiments, the mass ratio of mitotane, saline, serum albumin, and aspartic acid is 1:1100:110:2.1; and in some embodiments, mitotane, saline, serum albumin, and aspartic acid are... The mass ratio of physiological saline, serum albumin, and aspartic acid is 1:1200:120:2.2. In some embodiments, the mass ratio of mitotane, physiological saline, serum albumin, and aspartic acid is 1:1200:125:2.5. In some embodiments, the mass ratio of mitotane, physiological saline, serum albumin, and aspartic acid is 1:1300:105:3. In some embodiments, the mass ratio of mitotane, physiological saline, serum albumin, and aspartic acid is 1:1500:115:3.5. In some embodiments, the mass ratio of mitotane, physiological saline, serum albumin, and aspartic acid is 1:1800:120:4. In some embodiments, the mass ratio of mitotane, physiological saline, serum albumin, and aspartic acid is 1:2000:125:5, etc.

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

[0046] The lyophilized mitotane formulation of the present invention is prepared by the method described above; the lyophilized product comprises mitotane, serum-like substances, and amino acids, and also includes pharmaceutically acceptable inorganic substances. This lyophilized formulation exhibits good solubility, greatly increasing the solubility of mitotane, and also possesses the advantage of high stability.

[0047] Pharmaceutically acceptable inorganic substances include elements such as Na and Cl from physiological saline, as well as other pharmaceutical carriers such as sugars and esters.

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

[0049] The reconstitution method of the mitotane lyophilized formulation of the present invention involves mixing the above-mentioned mitotane lyophilized formulation with physiological saline, wherein each 50 mg of mitotane lyophilized formulation is reconstituted with at least 100 μl of physiological saline.

[0050] In the reconstituted solution obtained by the above method, the concentration of mitotane can reach 0.286–0.33 mg / ml, while the solubility of mitotane in physiological water is approximately 0.01 mg / 2.5 L (1 mg / 250 L), i.e., 4 × 10⁻⁶ mg / ml. -6 The concentration of mg / ml indicates that the solubility of mitotane in the reconstituted solution was significantly improved.

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

[0052] The pharmaceutical composition for treating cancer of the present invention includes the lyophilized mitotane formulation as described above, or the solution containing mitotane as described above.

[0053] Specifically, the cancer is adrenocortical carcinoma.

[0054] The present invention will be described below through specific embodiments.

[0055] Example 1

[0056] This embodiment uses the method of the present invention to prepare mitotane lyophilized formulation and then reconstitutes it. The specific steps are as follows:

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

[0058] (2) Prepare a 50 g / L human / bovine serum albumin solution: Take 1.25 g of human serum albumin, add 25 ml of physiological saline to dissolve, and shake well for later use.

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

[0060] (4) Preparation of a combination solution of mitotane, human / bovine serum albumin and amino acids: Take 10 ml of physiological saline in a beaker, add 25 ml of human / bovine serum albumin solution (50 g / L) and 30 mg of aspartic acid, stir until the aspartic acid dissolves, add 1 ml of mitotane ethanol stock solution, stir until homogeneous, and obtain a yellow clear liquid composition. The concentration of mitotane in this composition is 0.286 mg / ml.

[0061] (5) Preparation of a combination 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 well, add 1 ml of mitotane ethanol stock solution, stir well, and obtain a pale yellow clear liquid composition. In this composition, the concentration of mitotane is 0.26 mg / ml.

[0062] (6) Freeze-drying: The compositions obtained in steps (4) and (5) are dispensed into 10ml glass bottles and freeze-dried at -40℃ to obtain freeze-dried powder, which is then dispensed into 50ml centrifuge tubes.

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

[0064] Example 2 uses a mixture prepared from bovine serum and lyophilized powder.

[0065] (1) Prepare a 10 mg / ml mitotane ethanol solution: Take 20 mg mitotane into a 2 ml EP tube, add 2 ml 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, mitotane ethanol solution was added gradually until 1.2 mg was added, at which point a white precipitate was observed to form. In 10 ml of bovine serum, mitotane ethanol solution was added gradually until 12 mg was added before a white precipitate was observed to form. Therefore, bovine serum has a 10-fold greater solubilizing effect on mitotane ethanol solution than physiological saline.

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

[0068] Table 1

[0069] (4) Freeze-drying: The composition obtained in step (3) is dispensed into 10ml glass bottles and freeze-dried at -40℃ to obtain freeze-dried powder, which is then dispensed into 50ml centrifuge tubes.

[0070] (5) Reconstitution: The freeze-dried powder prepared using the above optimal ratio is reconstituted to the optimal concentration of 0.26 mg / ml. The room temperature stability can be improved to 24-48 h, and the clarity is also greatly improved.

[0071] (6) Comparison of the solubility of untreated mitotane powder and 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 simple physiological saline (0.004 mg / L).

[0072] Example 3 uses a mixture prepared from human serum and lyophilized powder.

[0073] Considering subsequent application issues, this embodiment uses human serum instead of bovine serum for the experiment.

[0074] (1) Preparation of 10 mg / mL mitotane ethanol solution: Take 20 mg mitotane into a 2 ml EP tube, add 2 ml ethanol, and shake well for later use.

[0075] (2) Comparison of the solubility of mitotane ethanol solution in human serum and physiological saline: In 10 ml of physiological saline, mitotane ethanol solution was added gradually until 1.2 mg was added, at which point a white precipitate was observed to form. In 10 ml of human serum, mitotane ethanol solution was added gradually until 12 mg was added before a white precipitate was observed to form. Therefore, the solubilizing effect of human serum on mitotane ethanol solution is consistent with that of bovine serum, and is also 10 times that of physiological saline.

[0076] (3) Preparation of the combined solution of mitotane ethanol and human serum: The optimal concentration of mitotane in physiological saline and human serum solution is 0.26 mg / ml, at which the solution exhibits the best clarity. At this concentration, the mass ratio of mitotane, physiological saline, and human serum is 1:2000:1755. Under this optimal mass ratio, the optimal dosages of mitotane ethanol solution, physiological saline, and human serum are 4 mg, 8 ml, and 7.3 ml, respectively, as shown in Table 2.

[0077] Table 2

[0078] (4) Freeze-drying: The composition obtained in step (3) is dispensed into 10ml glass bottles and freeze-dried at -40℃ to obtain freeze-dried powder, which is then dispensed into 50ml centrifuge tubes.

[0079] (5) Reconstitution: The lyophilized powder prepared using the above optimal ratio was most clear and had the longest stability time when reconstituted to 0.033 mg / ml, with a stability time of 6 days.

[0080] (6) Comparison of the maximum reconstitution concentration of lyophilized powders prepared using bovine serum and human serum: 50 mg of mitotane bovine serum lyophilized powder prepared in Example 2 can be reconstituted with a minimum of 200 μl of physiological saline, with a maximum reconstitution concentration of 250 mg / ml; while 50 mg of mitotane human serum lyophilized powder prepared in this example can be reconstituted with a minimum of 100 μl of physiological saline, with a maximum reconstitution concentration of 500 mg / ml. Therefore, compared with bovine serum, the lyophilized powder prepared using human serum has higher reconstitution properties.

[0081] Example 4: A mixture prepared using human / bovine serum albumin solution and lyophilized powder

[0082] 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 variations and high safety risks. Serum albumin, on the other hand, offers better cost-effectiveness, smaller batch-to-batch variations, 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.

[0083] (1) Preparation of 10 mg / mL mitotane ethanol solution: Take 20 mg mitotane into a 2 ml EP tube, add 2 ml ethanol, and shake well for later use.

[0084] (2) Prepare 50g / L human serum albumin solution and bovine serum albumin solution: Take 1.25g of human serum albumin and bovine serum albumin, add 25ml of physiological saline to dissolve them respectively, and shake well for later use.

[0085] (3) Comparison of the solubility of mitotane ethanol solution in human / bovine serum albumin solution (50 g / L) and physiological saline: In 10 ml of physiological saline, the above-mentioned mitotane ethanol solution was added gradually until 1.2 mg was added, at which point a white precipitate was observed to form. In 10 ml of human / bovine serum albumin solution (50 g / L), the above-mentioned mitotane ethanol solution was added gradually until 8.04 mg was added before a white precipitate was observed to form. Therefore, the solubilizing effect of 50 g / L human / bovine serum albumin solution on mitotane ethanol solution is 6.7 times that of physiological saline.

[0086] (4) Preparation of the combined 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, at which the solution exhibits the best clarity. At this concentration, the mass ratio of mitotane, physiological saline, and human / bovine serum albumin solution (50 g / L) is 1:1000:125. Under this optimal mass ratio, the optimal dosages of mitotane ethanol solution, physiological saline, and human / bovine serum albumin solution (50 g / L) are 1 mg, 1 ml, and 2.5 ml, respectively, as shown in Table 3.

[0087] Table 3

[0088] (5) Freeze-drying: The composition obtained in step (4) is dispensed into 10ml glass bottles and freeze-dried at -40℃ to obtain freeze-dried powder, which is then dispensed into 50ml centrifuge tubes.

[0089] (6) Reconstitution: Take 0.3432 g of lyophilized powder and add 10 ml of physiological saline to reconstitute. The concentration of mitotane in the reconstituted solution is 0.286 mg / mL. The lyophilized powder prepared using the above optimal ratio has the longest stability time of 7 days when reconstituted to 0.286 mg / mL.

[0090] Example 5: A mixture and lyophilized powder prepared using human / bovine serum albumin solution and amino acids.

[0091] To better simulate serum, this example examines the effect of adding amino acids on the solubility of mitotane, based on a human / bovine serum albumin solution. Aspartic acid was used as an example in this example.

[0092] (1) Preparation of 10 mg / mL mitotane ethanol solution: Take 20 mg mitotane into a 2 ml EP tube, add 2 ml ethanol, and shake well for later use.

[0093] (2) Prepare 50g / L human serum albumin solution and bovine serum albumin solution: Take 1.25g of human serum albumin and bovine serum albumin, add 25ml of physiological saline to dissolve them respectively, and shake well for later use.

[0094] (3) Preparation of a combination 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.

[0095] At this point, the mass ratio of mitotane, physiological saline, human / bovine serum albumin, and aspartic acid is 1:1000:125:2. Under this optimal mass ratio, the optimal dosages of mitotane ethanol solution, physiological saline, human / bovine serum albumin solution (50 g / L), and aspartic acid are 1 mg, 1 ml, 2.5 ml, and 3 mg, respectively, as shown in Table 4.

[0096] Table 4

[0097] (4) Freeze-drying: The composition obtained in step (4) is dispensed into 10ml glass bottles and freeze-dried at -40℃ to obtain freeze-dried powder, which is then dispensed into 50ml centrifuge tubes.

[0098] (5) Reconstitution: Take 0.3432 g of lyophilized powder and add 10 ml of physiological saline to reconstitute. The concentration of mitotane in the reconstituted solution is 0.286 mg / mL. The lyophilized powder prepared using the above optimal ratio has the longest stability time of 21 days when reconstituted to 0.286 mg / mL.

[0099] The experimental results above show that, without the addition of amino acids, the lyophilized powder prepared using human / bovine serum albumin at the optimal ratio and dosage has a stability time of 7 days when reconstituted to 0.286 mg / ml. However, after adding a certain amount of aspartic acid, the stability time at the same concentration is 21 days, indicating that mixing human / bovine serum albumin with amino acids further improves the solubility and stability of mitotane solution.

[0100] In the description of this invention, it should be noted that the terms "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0101] 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 principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing a lyophilized preparation of mitotane, characterized in that, Mitotan is dissolved in ethanol to obtain mitotane ethanol stock solution. A mixture containing the mitotane ethanol stock solution, physiological saline, serum solution and amino acids is prepared. The mixture is then freeze-dried to obtain the mitotane freeze-dried formulation. The serum solution includes one of human serum, bovine serum and serum albumin solution.

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

3. The method of claim 1, wherein the lyophilized mitotane formulation is prepared by, The serum solution is a serum albumin solution with a concentration of 40–55 g / L.

4. The method for preparing a lyophilized mitotane formulation 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 of claim 4, wherein the lyophilized mitotane formulation is prepared by, In the mixture, the mass ratio of mitotane, the saline, serum albumin, and amino acids is 1:1000-4000:100-150:2-8.

6. A method for preparing a mitotane lyophilized formulation according to any one of claims 1 to 5, characterized in that, It also includes the following steps: Add the serum solution and the amino acid to physiological saline, stir until the amino acid is completely dissolved, add the mitotane ethanol stock solution, stir until homogeneous, and obtain the mixture.

7. A lyophilized formulation of mitotane, characterized in that, It is prepared by the method described in any one of claims 1 to 6.

8. A method for reconstituting a lyophilized preparation of mitotane, characterized in that, The mitotane lyophilized formulation of claim 7 is mixed with physiological saline, wherein each 50 mg of the mitotane lyophilized formulation is reconstituted with at least 100 μl of physiological saline.

9. A solution containing mitotane, characterized in that, It is obtained by the reconstitution method as described in claim 8.

10. A pharmaceutical composition for treating cancer, comprising, The solution containing mitotane as described in claim 9 also includes pharmaceutically acceptable inorganic substances and carriers.

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