WO2012013116A1

WO2012013116A1 - Pharmaceutical composition of temozolomide comprising amino acid stabilizer and preparation method thereof

Info

Publication number: WO2012013116A1
Application number: PCT/CN2011/077093
Authority: WO
Inventors: 孙飘扬; 张辉; 吴玉霞
Original assignee: 江苏恒瑞医药股份有限公司
Priority date: 2010-07-29
Filing date: 2011-07-13
Publication date: 2012-02-02
Also published as: CN102481287B; WO2012013117A1; CN102342931B; CN102481288A; CN102481288B; CN102481287A; CN102342931A

Abstract

The present invention provides a pharmaceutical composition of temozolomide comprising amino acid stabilizer and a preparation method thereof. The pharmaceutical composition comprises temozolomide, or a pharmaceutically acceptable salt thereof, and at least one type of amino acid stabilizer. The amino acid stabilizer is selected from one or more analogs of L-alanine, L-glycine, and L-cysteine, or pharmaceutically acceptable salts thereof. The preparation method for the pharmaceutical composition comprises a step of mixing evenly the temozolomide or the pharmaceutically acceptable salt thereof with at least one amino acid stabilizer.

Description

Temozolomide pharmaceutical composition containing amino acid stabilizer and preparation method thereof

Technical field

The present invention relates to a stable temozolomide pharmaceutical composition comprising an antitumor drug temozolomide or a pharmaceutically acceptable salt thereof, at least one amino acid stabilizer. Background technique

Temozolomide chemical name: 3,4-dihydro-3-methyl-4-oxoimidazo[5,ld]-l,2,3,5-tetrazine-8-amide, is imidazotetra A purifying agent with antitumor activity, developed by Schering-Plough. Temozolomide is indicated for newly diagnosed glioblastoma multiforme, initially combined with radiotherapy, followed by adjuvant therapy; temozolomide is also indicated for glioblastoma or anaplastic star relapsed or progressed after conventional therapy Cell tumor. In 1998, temozolomide capsules were first marketed in the European Union and subsequently listed in the United States in 1999 with US FDA approval. Temozolomide is currently the first line of treatment for malignant brain tumors and has been evaluated by the United States and the European medical community as the "gold standard" for the treatment of malignant brain tumors.

At present, the domestic temozolomide market preparation is a hard capsule. The oral preparation is convenient to use, and can be completely absorbed after oral administration. The bioavailability is as high as 98%. The main side effects are nausea, vomiting, fatigue, constipation and mild myelosuppression, among which severe nausea, Side effects such as vomiting are common. This often causes fluctuations in drug absorption, which affects bioavailability. Some patients have nausea and vomiting reactions that are too severe to be administered orally, and many patients in the clinic have difficulty swallowing and cannot be administered orally. There is an urgent need for temozolomide preparations that can be administered intravenously. However, temozolomide is stable at pH<7, and easily decomposes at pH>7. Temozolomide is a prodrug and is easily degraded into an active product in aqueous solution. Preparation of a conventional intravenous solution does not guarantee long-term stability.

To achieve parenteral administration of temozolomide, a temozolomide formulation administered in a micronized suspension is disclosed in U.S. Patent No. 6,251,886, however, suspension formulations are not preferred and can cause vascular occlusion. Considering the unstable nature of temozolomide in aqueous solution, it is prepared by freeze-drying and solidification to prepare a sterile lyophilized powder. It is reconstituted with an aqueous diluent for injection before use to obtain a temozolomide injection which can be administered parenterally. , will be a good strategy. In addition, U.S. Patent No. 6,987,108 discloses a lyophilized powder injection of temozolomide for intravenous administration of temozolomide. The lyophilized powder of the above temozolomide can change from white to pale pink under long-term and accelerated conditions, which indicates that there may be some problems in its quality or stability. The change in the color of the lyophilized powder tends to make the patient suspect the quality of the drug and reduce the patient's compliance and acceptance. Therefore, it is necessary to study and develop a technique and a preparation thereof which can ensure the parenteral administration of temozolomide, which is stable and suitable for long-term preservation. Summary of the invention

SUMMARY OF THE INVENTION A primary object of the present invention is to provide a stable temozolomide pharmaceutical composition, and a process for its preparation. The inventors discovered through research that some amino acids have an effect of increasing the stability of temozolomide.

The present invention provides a pharmaceutical composition comprising temozolomide or a pharmaceutically acceptable salt thereof, and at least one amino acid stabilizer, wherein the amino acid stabilizer is selected from one or more L-alanines An L-glycine, a cysteine analog or a pharmaceutically acceptable salt thereof, wherein the cysteine analog is an amino acid having a cysteine main structure. Further, the pharmaceutical composition further comprises at least one aqueous diluent.

The structure of cysteine is as follows:

The cysteine analog can be structurally modified on the structure of cysteine, and the modification sites are a thiol group, a carboxyl group and an amino group. That is, cysteine analogs have the following cysteine main structure:

Specific cysteine analogs are selected from the group consisting of L-cysteine, L-cysteine hydrochloride, acetylcysteine, S-carboxymethyl-L-cysteine, L-cysteine One or more of ethyl acetate and L-cysteine methyl ester, preferably the analog is L-cysteine, L-cysteine hydrochloride or acetylcysteine, more preferably L-cysteine or L-cysteine hydrochloride, wherein L-cysteine hydrochloride includes anhydrate thereof and a hydrate such as L-cysteine hydrochloride monohydrate.

The invention can be made by using the pharmaceutical composition of temozolomide and amino acid stabilizer provided by the invention. An injectable parenteral pharmaceutical preparation, especially a pharmaceutical preparation in the form of a lyophilized powder.

The amino acid stabilizer based on the present invention has a stabilizing effect on temozolomide, and those skilled in the art will recognize that the addition of the amino acid stabilizer of the present invention will stabilize temozolomide. A preferred embodiment is that the weight ratio between temozolomide or a pharmaceutically acceptable salt thereof and an amino acid stabilizer is the following relationship in terms of temozolomide:

Amino acid stabilizer: the weight ratio of temozolomide or a pharmaceutically acceptable salt thereof is greater than

0.5:1;

Preferably, the amino acid stabilizer: temozolomide or a pharmaceutically acceptable salt thereof has a weight ratio greater than 0.8:1;

More preferably, the amino acid stabilizer: temozolomide or a pharmaceutically acceptable salt thereof is present in a weight ratio greater than 1.2:1;

Most preferably, the amino acid stabilizer: temozolomide or a pharmaceutically acceptable salt thereof has a weight ratio of more than 1.6:1.

The pharmaceutical composition may comprise one or more of an excipient, a wetting agent, a pH adjuster or a buffer, preferably the excipient is mannitol; the wetting agent is a polysorbate; The pH adjusting agent is hydrochloric acid; the buffering agent is selected from the group consisting of sodium citrate, acetic acid or acetate.

The present invention provides two specific embodiments in which the pharmaceutical composition contains the following components by weight or consists of the following components:

Embodiment 1

Temozolomide or its salt in terms of temozolomide 2.5 parts

L-cysteine or a salt thereof based on L-cysteine hydrochloride 4 parts Polysorbate - 80 3 parts Mannitol 15 parts Embodiment 2

Temozolomide or its salt in terms of temozolomide 2.5 parts

L-cysteine or its salt of L-cysteine hydrochloride 4 parts of mannitol 15 parts Further, the present invention also provides a process for preparing a pharmaceutical composition. The method of preparation comprises the step of uniformly mixing temozolomide or a pharmaceutically acceptable salt thereof with at least one amino acid stabilizer. 1) dissolving at least one amino acid stabilizer in an aqueous diluent to form a solution, preferably the solution temperature is controlled at 0-60 ° C;

2) Temozolomide or a pharmaceutically acceptable salt thereof is added to the above solution to dissolve.

The above preparation method specifically includes the following steps:

1) weighing a prescribed amount of a stabilizer, and optionally a wetting agent, excipient or buffer, stirring and dissolving in an aqueous diluent;

2) weighing a prescribed amount of temozolomide or a pharmaceutically acceptable salt thereof, stirring and dissolving in the above solution, and adjusting the pH value of the solution using a pH adjusting agent;

Preferably the pH is from 2.0 to 6.0, more preferably from 2.5 to 4.5, most preferably from 3.5 to 4.0;

3) Add the aqueous diluent to the final volume and mix well.

The aqueous diluent used in the above preparation method is selected from the group consisting of water, physiological saline, 5% dextrose solution or a mixture thereof.

The pharmaceutical composition of the present invention can be further prepared into a lyophilized powder preparation, and a mixed solution of temozolomide or a pharmaceutically acceptable salt thereof and a stabilizer is freeze-dried.

The present invention provides a pharmaceutical composition capable of ensuring the stability of temozolomide by the addition of an amino acid stabilizer. Surprisingly, for the temozolomide pharmaceutical composition represented by lyophilized powder, the amino acid stabilizer represented by cysteine monohydrate hydrochloride enhances the stability of temozolomide, which is not only guaranteed to ensure temozolomide The content and related substances were stable, and the color of the temozolomide composition which showed cysteine hydrochloride as a stabilizer under long-term and accelerated conditions did not change. The prepared temozolomide lyophilized powder injection maintains the appearance of white to off-white lyophilized powder, and the color of lyophilized powder becomes pale pink, and the change of color of temozolomide is an insurmountable difficulty in the use of medicines. The change in the color appearance of the drug will greatly reduce the credibility and compliance of the doctor and the patient.

Further studies have shown that this effect is related to the cysteine structure in amino acids. It has been experimentally proved that various amino acids having a cysteine main structure have similar effects. For example, cysteine has similar structural properties. : L-cysteine, L-cysteine hydrochloride anhydrate, L-cysteine hydrochloride monohydrate, acetylcysteine, S-carboxymethyl-L-cysteine Amino acid, L-cysteine ethyl ester hydrochloride, L-cysteine methyl ester hydrochloride, and amino acids having the same main structure and small difference in substituent groups can achieve a similar effect of stabilizing temozolomide. In the pharmaceutical composition of the present invention, the stabilizer is selected from the group consisting of L-cysteine, L-cysteine hydrochloride anhydrate, L-cysteine hydrochloride monohydrate, and acetyl half. Cystine or a mixture thereof. L-cysteine hydrochloride monohydrate is preferred.

The pharmaceutical composition of the present invention, wherein the content of the stabilizer is theoretically higher as possible, but for the preparation of the composition, various properties such as lyophilization process and molding are also considered, and various factors for the preparation of the composite composition are The total weight stabilizer is present in an amount ranging from 2% by weight to 60% by weight. Preferably, it is 5 wt% to 30 wt%; the pharmaceutical composition of the present invention, wherein the temozolomide or a pharmaceutically acceptable salt thereof is contained in an amount of 2 wt% to 60 wt% based on the total weight of the composition. It is preferably 5 wt% to 20 wt%.

In the preparation of the pharmaceutical composition of the present invention, at least one aqueous diluent is added, and the aqueous diluent is selected from the group consisting of water for injection, physiological saline, 5% dextrose solution or a mixture thereof.

Excipients which can be used in the present invention are selected from the group consisting of sodium chloride, glucose, lactose, mannitol, trehalose, xylitol, sucrose, sorbitol, dextrose, albumin, hydroxyethyl starch, cyclodextrin, glycine Or a mixture thereof, preferably mannitol; the wetting agent is selected from the group consisting of polysorbate, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, bile salt, lecithin, polyethylene glycol or a mixture thereof, preferably selected From polysorbate-20, polysorbate-40, polysorbate-60, polysorbate-80 or mixtures thereof, most preferably polysorbate-80; buffer selected from tannic acid Salt, lactate, acetate, tartrate, succinate, phosphate or mixtures thereof, preferably selected from the group consisting of citrates, acetates, phosphates or mixtures thereof, most preferably acetate or The pH adjusting agent is selected from the group consisting of hydrochloric acid, sodium hydroxide, citric acid, phosphoric acid, lactic acid, tartaric acid, succinic acid or a mixture thereof, preferably hydrochloric acid or acetic acid.

For excipients, buffers, conventional pH adjusting agents, buffers, those skilled in the art will be able to make selections and adjustments based on the lyophilized formulation preparation requirements.

In the injectable parenteral pharmaceutical preparation of the present invention, the excipient is preferably mannitol; the wetting agent is preferably polysorbate-80; and the conventional pH adjuster is preferably hydrochloric acid. The buffering agent is preferably sodium citrate, acetic acid and acetate.

The term "percent by weight" (wt%) used in the present invention is calculated on the basis of the total weight of the pharmaceutical composition.

The invention improves the temozolomide because of poor water solubility by the addition of a wetting agent, and is difficult to be The characteristics of water wetting and dissolution increase the dissolution rate of temozolomide, reduce the preparation time of the whole solution, reduce the time of temozolomide degradation in the solution, and thus reduce the degradation of temozolomide.

For the lyophilized powder injection preparation, the final formability of the temozolomide freeze-dried powder injection is ensured by the addition of the excipient, and the protective support of the excipient is ensured, and the temozolomide freeze-dried powder injection is reconstituted into a suitable patient. The time of preparation is greatly reduced. When the excipient is used in a pharmaceutical composition, its wt% may be from 20 wt% to 80 wt% based on the total weight of the pharmaceutical composition.

The addition of a buffering agent and a conventional pH adjusting agent in the present invention ensures that temozolomide reduces its degradation rate in a relatively low pH environment and a certain buffer system in a solution state. When the buffering agent is used in a pharmaceutical composition, its wt% may be from 5 wt% to 60 wt% based on the total weight of the pharmaceutical composition. When a conventional pH adjusting agent is used in a pharmaceutical composition, its wt% may be from 0.1 wt% to 20 wt% based on the total weight of the pharmaceutical composition.

The invention can reduce the degradation rate of temozolomide in the dissolution process and the solution state, thereby ensuring that temozolomide can be kept stable in a solution state for a long time, thereby facilitating the whole process of preparation, filling, freeze-drying, etc., and is easy to realize. Industrial production.

In the preparation method, the temperature should be appropriately controlled during the preparation of the chemical solution to reduce the degradation of temozolomide. detailed description

In order to clarify the invention, a formulation form of the lyophilized preparation is described as an example for comparison. The pharmaceutical compositions of the invention are typically prepared by the following steps:

Weigh the prescribed amount of stabilizer, wetting agent, excipient, and buffer. Stir and dissolve in the water for injection. The water is about 90% of the prescription amount, and the water temperature is controlled at 0-60 °C.

The prescribed amount of temozolomide is weighed, dissolved in the above solution, dissolved, and the pH of the solution is measured. The pH of the solution is adjusted to 3.5-4.5 as needed.

Water for injection is added to the final volume, and the solution is continuously stirred until it is well mixed.

The above solution was filtered and lyophilized. Example 1

Weigh 15.00 g of mannitol, 4.00 g L-cysteine hydrochloride monohydrate, 5.88 g Sodium citrate, add 900 mL of water for injection cooled to room temperature, stir to dissolve, adjust the pH of the solution to 3.7 with hydrochloric acid, add 2.50 g of temozolomide (Jiangsu Hengrui Pharmaceutical Co., Ltd., the same source in the following examples), stir and dissolve Add water to 1000 mL, filter with 0.22 μηι microporous membrane, freeze-dry, and obtain temozolomide lyophilized powder. Example 2

Weigh 15.00 g mannitol, 3.00 g polysorbate-80, 4.00 g L-cysteine hydrochloride monohydrate, 5.88 g sodium citrate, add 900 mL of water for injection cooled to room temperature, stir to dissolve The pH of the solution was adjusted to 3.7 with hydrochloric acid, 2.50 g of temozolomide was added, dissolved by stirring, water was added to 1000 mL, filtered through a 0.22 μηι microporous membrane, and lyophilized to obtain a temozolomide lyophilized powder. Example 3

Weigh 15.00 g mannitol, 3.00 g polysorbate-80, 2.00 g L-cysteine, 5.88 g sodium citrate, add 900 mL of water for injection cooled to room temperature, stir to dissolve, adjust the pH of the solution with hydrochloric acid To 3.7, 2.50 g of temozolomide was added, dissolved by stirring, water was added to 1000 mL, filtered through a 0.22 μηι microporous membrane, and lyophilized to obtain a temozolomide lyophilized powder. Example 4

Weigh 15.00 g of mannitol, 3.00 g of polysorbate-80, 4.00 g of acetylcysteine,

5.88 g sodium citrate, add 900 mL of water for injection cooled to room temperature, stir to dissolve, adjust the pH of the solution to 3.7 with hydrochloric acid, add 2.50 g of temozolomide, stir to dissolve, add water to 1000 mL, filter with 0.22 μηι microporous membrane Freeze-dried to obtain temozolomide lyophilized powder. Example 5

Weigh 3.00 g of polysorbate-80, 4.00 g of L-glycine, 10.00 g of mannitol, 5.67 g of acetic acid, 5.03 g of sodium acetate, add 900 mL of water for injection, stir to dissolve in a water bath at 40 ° C, and add 2.50 g of temozolomide. Stir and dissolve, add water to 1000 mL, filter with 0.22 μηι microporous membrane, dispense and freeze-dry to obtain temozolomide lyophilized powder. Example 6 Weigh 3.00 g polysorbate-80, 4.00 g L-alanine, 10.00 g mannitol, 5.67 g acetic acid, 5.03 g sodium acetate, add 900 mL water for injection, stir and dissolve in a water bath at 40 °C, add 2.50 g Temozolomide, dissolved by stirring, added with water to 1000 mL, filtered through a 0.22 μηι microporous membrane, dispensed, and lyophilized to obtain temozolomide lyophilized powder. Comparative Example 1 (conventional freeze-drying prescription)

Weigh 15.00 g mannitol, 5.88 g sodium citrate, add 900 mL of water for injection cooled to room temperature, stir to dissolve, adjust the pH of the solution to 3.7 with hydrochloric acid, add 2.50 g of temozolomide, stir to dissolve, add water to 1000 mL, use Filter through a 0.22 μηι microporous membrane and freeze-dry to obtain temozolomide lyophilized powder. Comparative example 2

Weigh 15.00 g mannitol, 3.00 g polysorbate -80, 5.88 g sodium citrate, add

900 mL of water for injection which has been cooled to room temperature, stir to dissolve, adjust the pH of the solution to 3.7 with hydrochloric acid, add 2.50 g of temozolomide, stir to dissolve, add water to 1000 mL, filter with 0.22 μηι microporous membrane, freeze-dry, and obtain temozolomide freeze-dried powder. Comparative Example 3 (U.S. Patent No. 6,987,108, Example 2)

Weigh 15.00 g mannitol, 3.00 g polysorbate-80, 4.00 g L-threonine, 5.88 g sodium citrate, add 900 mL of water for injection cooled to room temperature, stir to dissolve, adjust the pH of the solution with hydrochloric acid. 3.7, adding 2.50 g of temozolomide, stirring and dissolving, adding water to 1000 mL, filtering with 0.22 μηι microporous membrane, and lyophilizing to obtain temozolomide lyophilized powder. Stability comparison experiment one

A solution of temozolomide was prepared according to Example 2 and Comparative Example 3 (U.S. Patent No. 6,987,108, Example 2), and the prepared solution was freeze-dried to prepare a temozolomide freeze-dried powder injection. The solution stability of the solutions of Example 2 and Comparative Example 3 before lyophilization and the stability of the solution after reconstitution after lyophilization were respectively determined by reverse high performance liquid chromatography (HPLC). The results are shown in Table 1.

Table 1 Comparison of Example 2 and Comparative Example 3 (US6987108)

The results in the table indicate that the degradation rate of the solution state of the temozolomide of Example 2 before lyophilization in the present invention is similar to that of the formulation of U.S. Patent No. 6,987,108, and the degradation rate after reconstitution after lyophilization is lower than that of the formulation of U.S. Patent No. 6,987,108. Thus, the formulation of the present invention has better stability, and the addition of L-cysteine hydrochloride monohydrate can ensure the stability of temozolomide. Stability comparison experiment 2

The corresponding temozolomide solution was prepared according to the prescriptions of Examples 1, 2, 4 and Comparative Examples 1, 2, and 3, and lyophilized powder was prepared by freeze-drying. The prepared lyophilized powder was taken at 40 ° C for examination. The appearance and related substances of the samples after 5 days of storage were examined, and the relevant substances were determined by reversed-phase high performance liquid chromatography (HPLC). The results are shown in Table 2.

Table 2 Examples 1, 2, 4 prescriptions and comparative examples 1, 2, 3 appearance and related substances inspection time batch appearance related substances %

Example 1 White Loose Mass 0.06 Example 2 White Loose Mass 0.07 Example 4 White Loose Mass 0.15 Start

Comparative Example 1 White loose mass 0.06 Comparative Example 2 White loose mass 0.05 Comparative Example 3 White loose mass 0.22

5 days example 1 white loose block 0.06 Example 2 White Loose Block 0.07

Example 4 White Loose Mass 0.18 Comparative Example 1 Light Pink Loose Mass 1.09 Comparative Example 2 White Loose Mass 0.11 Comparative Example 3 White Loose Mass 0.23 Example 1 White Loose Mass 0.10 Example 2 White Loose block 0.09 Example 4 White loose block 0.18

10 days

Comparative Example 1 Light pink loose mass 1.32 Comparative Example 2 Light pink loose mass 0.11 Comparative Example 3 Light pink loose mass 0.25 From the results in the table, the freeze-dried powder obtained by the present invention has better stability. The lyophilized powder samples of Examples 1, 2, and 4 were surprisingly found to have no change in appearance and more excellent stability; while the lyophilized powders of Comparative Examples 1, 2, and 3 all showed significant color. Changes in appearance, changes in the color of the lyophilized powder indicate that the sample may have undergone significant changes, and changes in the appearance of the sample may reduce the compliance of the patient's medication, or even this indicates a poor stability of the sample. As can be seen from the above measurement results, the amino acid having a cysteine main structure has an effect of improving the stability of temozolomide, and L-cysteine or a salt thereof has the best effect. Stability comparison experiment three

The lyophilized powder prepared according to Example 2 and Comparative Example 3 (U.S. Patent No. 6,987,108, Example 2) was subjected to changes in related substances at 2-8 ° C, 25 ° C and 40 ° C, respectively. For stability investigation, the results are shown in Table 3, 4. Stability

2-8 °C 25 °C 40 °C time (M)

Related substances (%) Related substances (%) Related substances (%)

0 0.22 0.22 0.22

1 0.20 0.30 0.21 2 0.27 0.47 0.47 Table 4 Stability of temozolomide freeze-dried powder injection obtained in Example 2 of the present invention

2-8 °C 25 °C 40 °C time (M)

Related substances (%) Related substances (%) Related substances (%)

0 0.07 0.07 0.07

1 - 0.07 0.17

2 - 0.10 0.47

3 0.08 0.16 0.60

6 0.07 0.13 1.20 The results in Tables 3 and 4 show that the temozolomide lyophilized powder injection prepared in the present invention remains stable after 6 months, and the stability is superior to that of the temozolomide freeze-dried powder injection prepared by U.S. Patent No. 6,987,108. However, the temozolomide lyophilized powder injection prepared by US Pat. No. 6,987,108 has a color change from white or off-white to pale pink during the sample retention period, and the color is deepened and deepened, and this phenomenon also exists at 25 ° C; The color of the lyophilized powder did not change, leaving it white to white. This surprising result indicates that the temozolomide lyophilized powder injection prepared by the present invention has better stability.

Claims

Claims:

A pharmaceutical composition comprising temozolomide or a pharmaceutically acceptable salt thereof, and at least one amino acid stabilizer,

Wherein the amino acid stabilizer is selected from one or more of L-alanine, L-glycine, a cysteine analog or a pharmaceutically acceptable salt thereof, wherein the cysteine analog has The amino acid of the cysteine main structure.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises at least one aqueous diluent.

The pharmaceutical composition according to claim 1 or 2, wherein the cysteine analog is selected from the group consisting of L-cysteine, L-cysteine hydrochloride, acetylcysteine, One or more of S-carboxymethyl-L-cysteine, L-cysteine ethyl ester, L-cysteine methyl ester, preferably the cysteine analog is L- Cysteine, L-cysteine hydrochloride or acetylcysteine.

The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition is an injectable parenteral pharmaceutical preparation, preferably the pharmaceutical composition is in the form of a lyophilized powder.

The pharmaceutical composition according to any one of claims 1 to 4, wherein the content of the amino acid stabilizer is from 2% by weight to 60% by weight, preferably from 5% by weight to 30% by weight based on the total mass of the pharmaceutical composition.

The pharmaceutical composition according to any one of claims 1 to 5, wherein the temozolomide or a pharmaceutically acceptable salt thereof is contained in an amount of 2 wt% to 60 wt%, preferably 5 wt% to 20 wt%, based on the total mass of the pharmaceutical composition.

The pharmaceutical composition according to any one of claims 1 to 6, wherein the weight ratio between temozolomide or a pharmaceutically acceptable salt thereof and the amino acid stabilizer in terms of temozolomide satisfies the following relationship: Amino acid stabilizer: the weight ratio of temozolomide or a pharmaceutically acceptable salt thereof is greater than

0.5: 1 ;

Preferably, the amino acid stabilizer: temozolomide or a pharmaceutically acceptable salt thereof is present in a weight ratio greater than 0.8:1;

More preferably, the weight ratio of the amino acid stabilizer: temozolomide or a pharmaceutically acceptable salt thereof is greater than 1.2:1;

Most preferably, the amino acid stabilizer: temozolomide or a pharmaceutically acceptable salt thereof is present in a weight ratio greater than 1.6:1.

The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical composition further comprises one or more of an excipient, a wetting agent, a pH adjuster or a buffer.

9. The pharmaceutical composition according to claim 8, wherein the excipient is mannitol; the wetting agent is polysorbate-80; and the pH adjusting agent is hydrochloric acid; The buffer is selected from the group consisting of sodium citrate, acetic acid and acetate.

The pharmaceutical composition according to any one of claims 1 to 9, wherein the pharmaceutical composition contains the following components by weight, or consists of the following components by weight:

Temozolomide or its salt in terms of temozolomide 2.5 parts

L-cysteine or its salt 4 parts based on L-cysteine hydrochloride

Polysorbate - 80 3 parts

15 parts of mannitol.

The pharmaceutical composition according to any one of claims 1 to 9, wherein the pharmaceutical composition contains the following components by weight or consists of the following components by weight:

Temozolomide or its salt in terms of temozolomide 2.5 parts

L-cysteine or its salt 4 parts based on L-cysteine hydrochloride

15 parts of mannitol.

12. A method of preparing a pharmaceutical composition according to any of claims 1-11, comprising the step of uniformly mixing temozolomide or a pharmaceutically acceptable salt thereof with at least one amino acid stabilizer Step.

13. The method of claim 12 comprising the steps of:

1) dissolving at least one amino acid stabilizer in an aqueous diluent to form a solution, preferably the solution temperature is controlled at 0-60 ° C;

14. The method of claim 13 comprising the steps of:

1) weighing a prescribed amount of an amino acid stabilizer, and optionally a wetting agent, excipient or buffer, stirring and dissolving in an aqueous diluent;

3) Add the aqueous diluent to the final volume and mix well.

The method according to claim 13 or 14, wherein said aqueous diluent is selected from the group consisting of water, physiological saline, 5% dextrose solution or a mixture thereof.

The method according to any one of claims 13 to 15, further comprising the step of freeze-drying a mixed solution of temozolomide or a pharmaceutically acceptable salt thereof and a stabilizer to obtain a lyophilized powder.