Pharmaceutical composition containing temozolomide

Abstract

The invention relates to a solid pharmaceutical composition containing temozolomide. The solid pharmaceutical composition comprises temozolomide, a suspending aid, colloidal silicon dioxide and a pH regulator.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and particularly relates to a solid pharmaceutical composition containing temozolomide and its application. Background Art

[0002] Glioma is the most common primary central nervous system tumor in children and adolescents, accounting for 40% - 60% of all pediatric intracranial tumors. Among pediatric gliomas, WHO grade III or IV high-grade gliomas (HGG) account for about 8 - 12% of pediatric brain tumors, but they have a relatively high degree of malignancy, and the available treatment drugs are very limited, with a 5-year survival rate of less than 20%.

[0003] In the treatment of pediatric HGG, temozolomide remains an important treatment drug. The "Diagnosis and Treatment Specification for Pediatric Glioma (2021 Edition)" points out that the optional treatment regimens include temozolomide + lomustine. The "NCCN Clinical Practice Guidelines: Pediatric Central Nervous System Tumors (2023.V2)" in the United States, based on the COG ACNS0423 study, preferably recommends radiotherapy combined with temozolomide and lomustine for adjuvant treatment of pediatric HGG in children 3 years of age and older. In 2022, the working group on pediatric HGG of the Society for Pediatric Oncology in Europe (SIOPE) reached a consensus that all 32 countries agreed that pediatric hemispheric HGG should receive radiotherapy and adjuvant chemotherapy after surgical resection, and 30 (94%) of these countries recommended the use of temozolomide during initial radiotherapy.

[0004] The only commercially available oral formulation of temozolomide is a capsule formulation. The original research product was developed and marketed by Schering-Plough Corporation and is now marketed by Merck & Co., Inc. In January 1999, it was approved for marketing through the centralized review procedure in the European Union (trade name ); in August 1999, it was marketed in the United States (trade name ); in July 2006, it was marketed in Japan (trade name ); in 2008, the original research product was marketed in China (trade name or ). The marketed specifications of Merck & Co., Inc. in China and Japan are 20 mg and 100 mg.

[0005] The currently marketed temozolomide capsules are not suitable for the pediatric population, especially children under 6 years old, in terms of both the administration method (it is difficult for children to swallow capsules) and the flexibility of dose adjustment (administering according to body surface area). For pediatric patients who have difficulty swallowing temozolomide capsules in hospitals in Europe, the United States, and China, parents and caregivers need to open the capsules and mix the contents with soft food for administration. The stability of temozolomide when mixed with some foods is not good; there are literature reports that 4 food carriers (applesauce, chocolate cream, infant milk, mashed potatoes) have a significant impact on the stability of temozolomide, and the aminimidazolecarboxamide in 3 of these carriers increases significantly over time. Since children are in the stage of physical development, the dosage of medications is generally calculated according to the age, weight, or body surface area of children based on the adult dosage. Clinically, temozolomide is administered according to body surface area, while the temozolomide capsules marketed in China are in several fixed specifications.

[0006] To meet the clinical needs of patients, the United States Pharmacopeia has included the preparation method of temozolomide compounded oral suspension. The contents of temozolomide capsules, additional excipients (povidone PVP K30, citric acid), water, and the Ora-plus and Ora-Sweet solvents from Paddock Company are mixed to prepare an oral suspension for administration. The oral suspension should be stored in the refrigerator and used within 60 days. It needs to be shaken well before use. Since it is necessary to pour out the contents of the capsules, there is a risk of drug exposure. Therefore, it is required that this preparation process be carried out in a biosafety cabinet. Summary of the Invention

[0007] In the first aspect of the present invention, there is provided a solid pharmaceutical composition containing temozolomide, including temozolomide, a suspending agent, colloidal silicon dioxide, and a pH regulator;

[0008] The suspending agent is selected from one or more of xanthan gum, co-processed microcrystalline cellulose carboxymethylcellulose sodium, kappacarrageenan, gum arabic, pectin, corn starch, potato starch, rice starch, wheat starch, tapioca starch, sodium starch glycolate, pregelatinized starch, hydroxypropyl starch, guar gum, poloxamer, carbomer, alginic acid or its salts, hyaluronic acid or its salts; the mass ratio of the suspending agent to temozolomide is (1 - 20):40;

[0009] The mass ratio of the colloidal silicon dioxide to temozolomide is (1 - 50):40.

[0010] In one embodiment of the present invention, the solid pharmaceutical composition is exemplarily a dry suspension.

[0011] In one embodiment of the present invention, the suspending agent is preferably one or more of xanthan gum, microcrystalline cellulose carboxymethylcellulose sodium co-processed product, kappa-carrageenan, gum arabic, pectin, guar gum, alginic acid or its salts, hyaluronic acid or its salts. In one embodiment of the present invention, the suspending agent is more preferably one or more of xanthan gum, microcrystalline cellulose carboxymethylcellulose sodium co-processed product, kappa-carrageenan, gum arabic, pectin, guar gum. In one embodiment of the present invention, the suspending agent is further preferably xanthan gum, microcrystalline cellulose carboxymethylcellulose sodium co-processed product. In one embodiment of the present invention, the suspending agent is further preferably xanthan gum.

[0012] In one embodiment of the present invention, the mass ratio of the suspending agent to temozolomide is (1 - 5):40. In one embodiment of the present invention, the mass ratio of the suspending agent to temozolomide is (1 - 2):40. In one embodiment of the present invention, the mass ratio of the suspending agent to temozolomide is (2 - 3):40. In one embodiment of the present invention, the mass ratio of the suspending agent to temozolomide is (3 - 4):40. In one embodiment of the present invention, the mass ratio of the suspending agent to temozolomide is (4 - 5):40.

[0013] In one embodiment of the present invention, the mass ratio of colloidal silica to temozolomide is (1 - 20):40. In one embodiment of the present invention, the mass ratio of colloidal silica to temozolomide is (20 - 50):40. In one embodiment of the present invention, the mass ratio of colloidal silica to temozolomide is (1 - 10):40. In one embodiment of the present invention, the mass ratio of colloidal silica to temozolomide is (10 - 15):40. In one embodiment of the present invention, the mass ratio of colloidal silica to temozolomide is (15 - 20):40.

[0014] In one embodiment of the present invention, the pH regulator is a pharmaceutically acceptable organic acid in solid form at room temperature. In one embodiment of the present invention, preferably, the pH regulator is selected from one or more of citric acid, tartaric acid, metatartaric acid, malic acid, fumaric acid, succinic acid, maleic acid. In one embodiment of the present invention, more preferably, the pH regulator is citric acid. In one embodiment of the present invention, the mass ratio of the pH regulator to temozolomide is (0.1 - 3):40. In one embodiment of the present invention, the mass ratio of the pH regulator to temozolomide is (3 - 10):40. In one embodiment of the present invention, the mass ratio of the pH regulator to temozolomide is (0.1 - 1):40. In one embodiment of the present invention, the mass ratio of the pH regulator to temozolomide is (0.1 - 0.7):40. In one embodiment of the present invention, the mass ratio of the pH regulator to temozolomide is (0.3 - 0.7):40. In one embodiment of the present invention, the mass ratio of the pH regulator to temozolomide is (0.7 - 1.1):40. In one embodiment of the present invention, the mass ratio of the pH regulator to temozolomide is (1.1 - 1.5):40. In one embodiment of the present invention, the mass ratio of the pH regulator to temozolomide is (1.5 - 1.9):40. In one embodiment of the present invention, the mass ratio of the pH regulator to temozolomide is (1.9 - 2.3):40. In one embodiment of the present invention, the mass ratio of the pH regulator to temozolomide is (2.3 - 2.7):40. In one embodiment of the present invention, the mass ratio of the pH regulator to temozolomide is (2.7 - 3):40. In one embodiment of the present invention, when the solid pharmaceutical composition is mixed with water, the mass-to-volume ratio of temozolomide to water in the resulting liquid is 40 mg:(10 - 40) mL, and the pH of the liquid is 2 - 6. In one embodiment of the present invention, when the solid pharmaceutical composition is mixed with water, the mass-to-volume ratio of temozolomide to water in the resulting liquid is 40 mg:(10 - 40) mL, and the pH of the liquid is 2 - 5.

[0015] The pH regulator (such as citric acid, tartaric acid, metatartaric acid, malic acid, fumaric acid, succinic acid, maleic acid) can be in the form of a hydrate or an anhydride; if it is in the form of a hydrate, when calculating the mass ratio of the pH regulator to temozolomide, it should be converted to the anhydride form.

[0016] In one embodiment of the present invention, the solid pharmaceutical composition further comprises one or more of a sweetening agent, a flavoring agent, and an antibacterial agent.

[0017] In one embodiment of the present invention, the sweetener is selected from one or more of sucrose, sucralose, mannitol, glucose, fructose, aspartame, xylitol, maltitol, sorbitol, fructooligosaccharide, stevioside, and sodium saccharin. In one embodiment of the present invention, the sweetener is preferably one or more of sucralose, aspartame, stevioside, and sodium saccharin. In one embodiment of the present invention, the sweetener is more preferably sucralose. Preferably, the mass percentage of the sweetener in the pharmaceutical composition is 0.05% - 6%, or 0.2% - 6%, or 0.8% - 6%, or 1.6% - 6%, or 1.6% - 5%, or 1.6% - 3%.

[0018] In one embodiment of the present invention, the essence is a solid essence. Exemplarily, in some embodiments, the essence produces strawberry flavor, orange flavor, lemon flavor, cherry flavor, apple flavor, orange flavor, mint flavor, raspberry flavor, banana flavor, cola flavor, vanilla flavor, or caramel flavor.

[0019] In one embodiment of the present invention, the bacteriostatic agent is selected from one or more of chlorobutanol, methylparaben, sodium methylparaben, ethylparaben, sodium ethylparaben, propylparaben, sodium propylparaben, benzoic acid, sodium benzoate, potassium metabisulfite, sodium metabisulfite, sodium sulfite, sodium bisulfite, sodium hydrosulfite, ε-polylysine, ε-polylysine hydrochloride, sorbic acid, and potassium sorbate.

[0020] In the second aspect of the present invention, a suspension containing temozolomide is provided, which is formed by mixing the solid pharmaceutical composition described in the first aspect of the present invention with water.

[0021] In one embodiment of the present invention, the mass-to-volume ratio of temozolomide to water in the suspension is 40mg:(10 - 40)mL. In one embodiment of the present invention, the mass-to-volume ratio of temozolomide to water in the suspension is preferably 40mg:(15 - 30)mL. In one embodiment of the present invention, the mass-to-volume ratio of temozolomide to water in the suspension is preferably 40mg:15mL, or 40mg:20mL, or 40mg:25mL, or 40mg:30mL.

[0022] In one embodiment of the present invention, the pH of the suspension is 2 - 6. In one embodiment of the present invention, the pH of the suspension is preferably 2 - 5.

[0023] In the third aspect of the present invention, an application of the solid pharmaceutical composition described in the first aspect of the present invention in the preparation of a drug is provided, and the drug is used for the treatment of tumors. The tumor is preferably glioma.

[0024] In a fourth aspect of the present invention, there is provided a method for preparing the solid pharmaceutical composition described in the first aspect of the present invention: mixing the raw and auxiliary materials and then dividing them into pharmaceutical containers.

[0025] Exemplarily, the pharmaceutical container is an oral liquid pharmaceutical polyester bottle, an oral pharmaceutical high-density polyethylene press-on cap (including a sealing gasket) and an oral pharmaceutical low-density polyethylene bottle stopper packaging; the outside of the bottle is packaged with a polyester / aluminum / polyethylene composite bag for pharmaceutical packaging. Optionally, a desiccant is contained in the composite bag. Optionally, an oral dispenser is contained in the composite bag or the composite bag is packaged in combination with an oral dispenser; it can be, for example, a 10 mL oral dispenser.

[0026] In the present invention, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that, within the scope of sound medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0027] In the present invention, the term "flavor" refers to a blending mixture composed of a fragrance and fragrance adjuvants (optional) used to impart a fragrance; the flavor may or may not contain fragrance adjuvants. The term "fragrance" refers to a substance added to a drug or food to generate, modify or enhance a fragrance; including but not limited to natural fragrance substances, natural fragrance complexes, synthetic fragrances, etc.

[0028] In the present invention, the term "bacteriostatic agent", also known as preservative, is a class of substances that prevent product spoilage and extend the storage period of the product. Parabens, commonly known as nipagin esters, are a kind of safe, highly effective and broad-spectrum food preservatives; including their methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, pentyl ester, heptyl ester, octyl ester, etc.

[0029] In the present invention, the term "containing" or "including (comprising)" can be open-ended, semi-closed and closed-ended. In other words, the term also includes "substantially consisting of..." or "consisting of...".

[0030] In the present invention, the term "room temperature" refers to 15 - 25 °C.

[0031] In the present invention, "mass / volume percentage" or "%(w / v)" or "% w / v" is a way of expressing mass / volume concentration, indicating the number of grams of solute contained in every 100 ml of solution. For example, 20%(w / v) means that every 100 ml of solution contains 20 g of solute.

[0032] The solid pharmaceutical composition and suspension containing temozolomide provided by the present invention can improve the administration compliance and convenience. The solid pharmaceutical composition containing temozolomide provided by the present invention can be suspended in a short time after being shaken after being mixed with water to form a suspension. The solid pharmaceutical composition containing temozolomide provided by the present invention has excellent stability; after the solid pharmaceutical composition is mixed with water to form a suspension, excellent stability is maintained during the temporary use period. Detailed implementation mode

[0033] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer.

[0034] Example 1

[0035] Weigh appropriate amounts of excipients according to Table 1, add appropriate amounts of purified water (the amount of excipients in Table 1 corresponds to 20 mL of purified water), stir evenly, and then measure the viscosity.

[0036] Weigh 800 mg of temozolomide, mix it with the excipients in Table 1 respectively, add it to a vial; add 20 mL of purified water, shake it manually for 1 minute, and observe the dispersion phenomenon.

[0037] The data in Table 1 show that when xanthan gum is used as a suspending agent, temozolomide can be dispersed as a suspension.

[0038] Table 1

[0039] Excipients Viscosity mPa·s Phenomenon Hydroxypropylmethylcellulose K15M 200mg 638 Dispersion failure Hydroxypropylmethylcellulose K4M 200mg 316 Dispersion failure Sodium carboxymethylcellulose 400mg 314 Dispersion failure Hydroxypropylcellulose HF 100mg 314 Dispersion failure, insoluble Hydroxypropylcellulose MF 200mg 50 Dispersion failure, insoluble Xanthan gum 40mg 174 Dispersed within 1 minute

[0040] 0.2% hydroxyethyl cellulose (HEC 250HX) and 0.4% hydroxyethyl cellulose (HEC 250M) were further tested, and the observed phenomenon was dispersion failure. The microcrystalline cellulose carboxymethylcellulose sodium co-processed product was further tested, and dispersion was observed in about 1 minute.

[0041] Example 2

[0042] Weigh appropriate amounts of excipients according to Table 2, add appropriate amounts of purified water (the amount of excipients in Table 2 corresponds to 20 mL of purified water), stir evenly, and then measure the viscosity.

[0043] Weigh 800 mg of temozolomide, mix it with the excipients in Table 2 respectively, add it to a vial; add 20 mL of purified water, shake it manually for 1 minute, and observe the dispersion phenomenon.

[0044] The data in Table 2 show that by combining colloidal silica and xanthan gum, the usable concentration of xanthan gum can be increased, and at the same time, the stability of the suspending agent can be synergistically increased, and the sedimentation rate can be slowed down.

[0045] Table 2

[0046]

[0047]

[0048] Example 3

[0049] Weigh 800 mg of temozolomide and 100 mg of xanthan gum, mix them and add them into a bottle; add 20 mL of purified water and shake manually for 1 minute. It is observed that there are many particles in the liquid.

[0050] Weigh 800 mg of temozolomide, 100 mg of xanthan gum and the corresponding other excipients (shown in Table 3), mix them and add them into a bottle.

[0051] Table 3

[0052] 3-1# 3-2# Temozolomide / mg 800 800 Xanthan gum / mg 100 100 Colloidal silica / mg 20 200 Citric acid / mg 100 100 Sucralose / mg 20 20 Fragrance / mg 20 20

[0053] Measure 20 mL of purified water, add it into the bottle, and shake manually for 1 minute. Place it in the refrigerator (2 - 8 °C), and after one week and two weeks, observe the appearance and determine the content of temozolomide; the results are shown in Table 4. The data in Table 4 show that by combining colloidal silica and xanthan gum, the available concentration of xanthan gum can be increased, and at the same time, the stability of the suspension can be synergistically increased, and the sedimentation rate can be slowed down.

[0054] Table 4

[0055]

[0056] Examples 4 - 7

[0057] Weigh temozolomide and the corresponding excipients (shown in Table 5), mix them and add them into a bottle.

[0058] Table 5

[0059]

[0060]

[0061] Measure 20 mL of purified water, add it into the bottle, and shake manually for 1 minute. Observe the appearance on the 0th day, determine the content of temozolomide, and measure the pH of the liquid; the results are shown in Table 6. Place it in the refrigerator (2 - 8 °C), and after one week, observe the appearance and determine the content of temozolomide; the results are shown in Table 6.

[0062] Table 6

[0063]

[0064] Example 8

[0065] Prepare temozolomide dry suspension samples according to the prescription of 800 mg of temozolomide, 40 mg of xanthan gum, 600 mg of colloidal silicon dioxide, and 100 mg of citric acid per bottle.

[0066] Add 20 ml of purified water to the sample to make it into a suspension, and prepare a suspension containing 40 mg / ml of the drug. Let it stand for 4 weeks. The solution is uniform. The main inspection indicators are shown in Table 7. After standing for 1 week, the appearance of the product is uniformly suspended without stratification or discoloration, and there are no obvious changes in the drug content and related substances, which can support clinical use (a single treatment cycle of 5 days).

[0067] Table 7

[0068]

[0069] Example 9

[0070] Prepare temozolomide dry suspension samples according to the prescription in Table 8 respectively.

[0071] Table 8

[0072] 9-1# 9-2# 9-3# Temozolomide / mg 800 800 800 Xanthan gum / mg 36 36 40 Colloidal silica / mg 200 200 200 Anhydrous citric acid / mg 10 10 10 Sucralose / mg 20 20 20 API particle size D90 = 35μm D90 = 75μm D90 = 35μm

[0073] Add 20 ml of purified water to the sample to make it into a suspension, and prepare a suspension containing 40 mg / ml of the drug. After manually shaking for 1 minute, let it stand for 5 minutes, and then pass through a 20-mesh sieve and a 32-mesh sieve respectively; according to the experimental device of the second method for dissolution determination in the fourth part of the Chinese Pharmacopoeia (2020 Edition), using water as the dissolution medium, the rotation speed is 100 rpm, the volume of the dissolution medium is 500 ml, place it in the dissolution basket, and determine the cumulative dissolution percentage of the suspension; the results are shown in Table 9.

[0074] Table 9

[0075]

[0076] The data in Table 9 show that the viscosities of the three groups all reach a relatively stable state at 5 minutes, with little difference, and the sedimentation volume ratios all meet the requirements, and there is no difference in the dissolution behavior.

[0077] Example 10

[0078] Prepare temozolomide dry suspension samples according to the prescription in Table 10.

[0079] Table 10

[0080] 10-1# 10-2# 10-3# Temozolomide / mg 800 800 800 Xanthan gum / mg 40 40 40 Colloidal silica / mg 200 260 320 Anhydrous citric acid / mg 10 10 10 Sucralose / mg 20 20 20

[0081] The samples were subjected to stability studies. The conditions for accelerated stability were a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5%. The conditions for high-temperature stability were a temperature of 60°C ± 2°C. After reaching the corresponding study time, the corresponding samples were taken, 20 ml of purified water was added to the samples to make them into a suspension, and a suspension containing 40 mg / ml of the drug was prepared for performance testing. The main test indicators are shown in Table 11.

[0082] Table 11

[0083]

[0084] The data in Table 11 show that after 3 months under accelerated conditions and 1 month under high-temperature conditions, the content of impurity B in groups 10-2# and 10-3# increased slightly with the increase in the amount of colloidal silica used. The results in Table 11 show that from the perspective of stability, when the amount of colloidal silica used meets the quality requirements of the samples, a lower amount is preferably selected.

[0085] Example 11

[0086] According to the prescription in Table 12, temozolomide dry suspension samples were prepared.

[0087] Table 12

[0088]

[0089] The samples were subjected to stability studies. The conditions for accelerated stability were a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5%. The conditions for high-temperature stability were a temperature of 60°C ± 2°C. After reaching the corresponding study time, the corresponding samples were taken, 20 ml of purified water was added to the samples to make them into a suspension, and a suspension containing 40 mg / ml of the drug was prepared for performance testing. The main test indicators are shown in Table 13.

[0090] Table 13

[0091]

[0092] The data in Table 13 show that with the increase in the amount of acidic excipients used, the sedimentation volume ratio of the samples decreased. Therefore, a smaller amount of acidic excipients is preferably selected. Experiments have shown that when the anhydrous citric acid is 2 mg (corresponding to 800 mg of temozolomide), it has no adverse effect on the related substances (data not shown).

[0093] Example 12

[0094] According to the prescription in Table 14, temozolomide dry suspension samples were prepared.

[0095] Table 14

[0096] Temozolomide / mg 800 Xanthan gum / mg 36 Colloidal silica / mg 200 Anhydrous citric acid / mg 10 Sucralose / mg 20

[0097] Add 20 ml of purified water to the sample to make a suspension, and prepare a suspension containing 40 mg / ml of the drug. Then, sample using a 10-ml oral dispenser assembled for clinical use to investigate the dose accuracy in the vial at the same dose of 100 mg (2.5 ml). The results are shown in Table 15; the results show good dose accuracy.

[0098] Table 15

[0099]

[0100] Add 20 ml of purified water to the sample to make a suspension, and prepare a suspension containing 40 mg / ml of the drug. Then, open the vial and take the medicine using a 10-ml oral dispenser assembled for clinical use; take 10 portions of 10 mL of the suspension respectively. The average content of the 10 samples at day 0 is 396.1 mg (RSD is 0.61%), and the average value is 401.1 mg (RSD is 1.3%) after standing for 7 days. Take 10 portions of 2.5 mL of the suspension respectively. The average content of the 10 samples at day 0 is 96.0 mg (RSD is 0.96%), and the average value is 99.8 mg (RSD is 0.96%) after standing for 7 days. Take 10 portions of 1 mL of the suspension respectively. The average content of the 10 samples at day 0 is 38.1 mg (RSD is 0.92%), and the average value is 40.7 mg (RSD is 1.2%) after standing for 7 days. Take 10 portions of 0.25 mL of the suspension respectively. The average content of the 10 samples at day 0 is 9.7 mg (RSD is 18.57%), and the average value is 10.6 mg (RSD is 3.7%) after standing for 7 days. The results show good dose accuracy.

[0101] Example 13

[0102] Prepare temozolomide dry suspension samples according to the prescription of 800 mg of temozolomide, 40 mg of xanthan gum, 200 mg of colloidal silicon dioxide, 10 mg of citric acid, and 20 mg of sucralose per vial.

[0103] Add 20 ml of purified water to the sample to make a suspension, and prepare a suspension containing 40 mg / ml of the drug; store it in a refrigerator at 2 - 8°C and investigate for 1 week and 5 weeks. Among them, after the suspension is sampled for 1 week, the test results of aerobic bacteria, molds and yeasts, Escherichia coli, and Burkholderia cepacia meet the requirements; after the suspension is sampled for 5 weeks, the test results of aerobic bacteria, Escherichia coli, and Burkholderia cepacia meet the requirements.

[0104] The pharmaceutical composition of the present invention is in solid form during storage and is only in suspension form for a short time during use. Based on the investigation results of the suspension, the bacteriostatic agent is an optional but not essential component in the pharmaceutical composition of the present invention.

[0105] Example 14

[0106] Three batches of temozolomide dry suspension samples were prepared according to the prescription containing 800 mg of temozolomide, 36 mg of xanthan gum, 200 mg of colloidal silicon dioxide, 10 mg of citric acid, and 20 mg of sucralose per bottle.

[0107] The samples were packaged using oral liquid medicinal polyester bottles, oral medicinal high-density polyethylene press-on screw caps (including sealing gaskets), and oral medicinal low-density polyethylene bottle stoppers; the outside of the bottle was packaged with a polyester / aluminum / polyethylene composite bag for pharmaceutical packaging. The accelerated stability test was carried out, and after 3 months of stability investigation, no obvious changes occurred in various indicators.

[0108] All documents mentioned in the present invention are cited in this application for reference as if each document was cited separately for reference. In addition, it should be understood that after reading the above content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims

1. A solid pharmaceutical composition containing temozolomide, characterized in that: Including temozolomide, suspending agent, colloidal silicon dioxide, pH regulator; The suspending agent is selected from one or more of xanthan gum, microcrystalline cellulose and sodium carboxymethyl cellulose co-processed product, kappa carrageenan, gum arabic, pectin, corn starch, potato starch, rice starch, wheat starch, tapioca starch, sodium starch glycolate, pregelatinized starch, hydroxypropyl starch, guar gum, poloxamer, carbomer, alginic acid or its salt, hyaluronic acid or its salt; the mass ratio of the suspending agent to temozolomide is (1-20):40; The mass ratio of the colloidal silicon dioxide to temozolomide is (1-50):

40.

2. The pharmaceutical composition according to claim 1, characterized in that The mass ratio of the suspending agent to temozolomide is (1-5):40; Preferably, the mass ratio of the suspending agent to temozolomide is (1-2):40, or (2-3):40, or (3-4):40, or (4-5):

40.

3. The pharmaceutical composition according to claim 1, characterized in that The mass ratio of the colloidal silicon dioxide to temozolomide is (1-20):40, or (20-50):40; Preferably, the mass ratio of the colloidal silicon dioxide to temozolomide is (1-10):40, or (10-15):40, or (15-20):

40.

4. The pharmaceutical composition according to claim 1, characterized in that The pH adjuster is a pharmaceutically acceptable organic acid in solid form at room temperature; Preferably, the pH regulator is selected from one or more of citric acid, tartaric acid, metatartaric acid, malic acid, fumaric acid, succinic acid, and maleic acid; Preferably, the mass ratio of the pH regulator to temozolomide is (0.1-3):40 or (3-10):40; more preferably, the mass ratio of the pH regulator to temozolomide is (0.1-1):40, or (0.1-0.7):40; Preferably, when the solid pharmaceutical composition is mixed with water, the mass volume ratio of temozolomide to water in the mixed liquid is 40 mg: (10-40) mL, and the pH of the liquid is 2-6.

5. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that The composition further comprises one or more of a sweetener, a flavor, and an antibacterial agent.

6. The pharmaceutical composition according to claim 5, characterized in that The sweetener is selected from one or more of sucrose, sucralose, mannitol, glucose, fructose, aspartame, xylitol, maltitol, sorbitol, oligofructose, steviol glycoside, and saccharin sodium; Preferably, the mass percentage of the sweetener in the pharmaceutical composition is 0.05% to 6%, or 0.2% to 6%, or 0.8% to 6%, or 1.6% to 6%, or 1.6% to 5%, or 1.6% to 3%.

7. The pharmaceutical composition according to claim 5, characterized in that The essence is a solid essence.

8. The pharmaceutical composition according to claim 5, characterized in that The antibacterial agent is selected from one or more of chlorobutanol, methyl parahydroxybenzoate, sodium methyl parahydroxybenzoate, ethyl parahydroxybenzoate, sodium ethyl parahydroxybenzoate, propyl parahydroxybenzoate, sodium propyl parahydroxybenzoate, benzoic acid, sodium benzoate, potassium metabisulfite, sodium metabisulfite, sodium sulfite, sodium bisulfite, sodium hyposulfite, ε-polylysine, ε-polylysine hydrochloride, sorbic acid, and potassium sorbate.

9. A suspension containing temozolomide, which is prepared by mixing the solid pharmaceutical composition according to any one of claims 1 to 8 with water; The mass volume ratio of temozolomide to water in the suspension is 40 mg: (10-40) mL.

10. The suspension according to claim 9, characterized in that The pH of the suspension is 2-6; preferably, the pH of the suspension is 2-5.

11. Use of the solid pharmaceutical composition according to any one of claims 1 to 8 in the preparation of a drug for the treatment of tumors.

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