A temozolomide formulation and a method of preparing the same

Abstract

The present application provides a preparation method of temozolomide preparation, comprising the following steps: A) adding sodium carboxymethyl starch, tartaric acid, colloidal silicon dioxide and part of anhydrous lactose into a compulsory mixer, then adding stearic acid and the rest of anhydrous lactose into the mixer in sequence after sieving, and mixing uniformly; B) adding temozolomide into the compulsory mixer, mixing uniformly, and filling capsules. The present application changes the adding time of stearic acid, simultaneously uses compulsory mixing in the preparation process, makes stearic acid uniformly distribute in the excipients, reduces the moisture absorption of the moisture-absorbing material, and then shows the overall moisture absorption reduction in the preparation, so as to achieve the effect of reducing the requirement of the preparation production on the environmental humidity while ensuring the dissolution stability.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, and particularly relates to a temozolomide formulation and its preparation method. Background Technology

[0002] Temozolomide, chemical name: 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-asymmetric-tetrazolium-8-amide, has the following structural formula:

[0003]

[0004] Temozolomide capsules were approved for marketing in the European Union in January 1999. Their excipients are anhydrous lactose, sodium carboxymethyl starch, tartaric acid, colloidal silica, and stearic acid. Patent application 00805865.2 (publication number CN1345240A) discloses the formulation of temozolomide capsules, as shown in Table 1.

[0005] Table 1: Temozolomide Capsule Formulations

[0006] Temozolomide 5 20 100 250 Anhydrous lactose 132.8 182.2 175.7 154.3 Sodium carboxymethyl starch (formerly sodium glycolate starch) 7.5 11.0 15.0 22.5 Colloidal silica 0.2 0.2 0.3 0.7 tartaric acid 1.5 2.2 3.0 9.0 stearic acid 3.0 4.4 6.0 13.5

[0007] Temozolomide is a white, light brown, or pale pink powder, odorless, slightly soluble in water and dimethyl sulfoxide, and soluble in hot water. Its solubility in water is approximately 3.1 mg / mL, but the dissolution rate is slow, and it is easily degraded in water. As is well known, degradation of a formulation is accompanied by other stability issues. For temozolomide capsules, currently marketed products all exhibit stability problems such as rapid growth of total impurities during storage and a slowing of dissolution over time.

[0008] To address the aforementioned formulation issues, patent application 201710633102.0 (publication number CN107397735A) disclosed a scheme involving the replacement of some excipients, such as replacing sodium carboxymethyl cellulose with sodium carboxymethyl starch, glyceryl behenate with stearic acid, and silica with colloidal silica. The preparation process involves mixing the API (temozolomide) with excipients other than the lubricant, then adding the lubricant (glyceryl behenate, etc.), mixing thoroughly, and finally filling into capsules. However, the temozolomide capsules prepared according to this patented process showed a significant degradation trend under accelerated stability testing (40℃, 75% RH), with impurities increasing very rapidly, exceeding 19 times the total impurities from 0 to 6 months. Furthermore, the sample dissolution rate also showed a significant decreasing trend over time, indicating poor formulation stability.

[0009] In addition, temozolomide is very sensitive to moisture. The formulation contains sodium carboxymethyl starch and tartaric acid, which are highly hygroscopic. The material system may absorb moisture, resulting in a moisture content exceeding 2.0%. When the moisture content increases, the color of the temozolomide powder will darken. This phenomenon is mainly due to the degradation of temozolomide when it comes into contact with water.

[0010] To address the issue of temozolomide capsules' hygroscopic degradation, the formulation process requires strict control of environmental humidity (relative humidity below 40%). However, the above-mentioned non-standard GMP process environmental humidity control requirements place high demands on the air conditioning system.

[0011] Therefore, there is an urgent need for a preparation process that can improve the stability and dissolution effect of temozolomide. Summary of the Invention

[0012] To address the significant slowdown in dissolution rate of existing temozolomide formulations after accelerated and long-term stability testing, this invention aims to provide a temozolomide formulation and its preparation method. The preparation method of this invention can improve the dissolution stability of temozolomide formulations, reduce the requirements for humidity control in the formulation process environment, reduce intra-batch and inter-batch differences, and improve process robustness.

[0013] This invention provides a method for preparing a temozolomide formulation, comprising the following steps:

[0014] A) Add sodium carboxymethyl starch, tartaric acid, colloidal silica, and some anhydrous lactose into a forced mixer. Then, sieve the stearic acid and the remaining anhydrous lactose and add them into the mixer. Mix well.

[0015] B) Add temozolomide to a forced mixer, mix well, and fill into capsules.

[0016] Preferably, the component ratios in the temozolomide formulation, by weight, are as follows: temozolomide 5-250 parts, anhydrous lactose 132-183 parts, sodium carboxymethyl starch 7-23 parts, colloidal silica 0.2-0.7 parts, tartaric acid 1.5-9 parts, and stearic acid 3-14 parts. Preferably, the stearic acid is one or more of type 50 stearic acid, type 70 stearic acid, and type 95 stearic acid.

[0017] Preferably, in step A), the amount of lactose used is half to two-thirds of the total amount of lactose used.

[0018] Preferably, in step A), stearic acid is passed through an 18-60 mesh sieve, and then the sieve is washed with the remaining anhydrous lactose.

[0019] Preferably, in step A), the stirring speed of the forced mixer is 200-400 rpm, the cutting speed is 700-1000 rpm, and the mixing time is 10-20 min.

[0020] Preferably, in step B), the stirring speed of the forced mixer is 200-400 rpm, the cutting speed is 400-600 rpm, and the mixing time is 3-7 min.

[0021] Preferably, the ambient humidity during the preparation process is required to be ≤50%.

[0022] Preferably, in step B), a tube-type capsule filling machine equipped with a vacuum suction groove is used for filling.

[0023] Preferably, the vacuum degree of the filling is -0.3 to -0.6 bar.

[0024] This invention provides a temozolomide formulation prepared by the method described above.

[0025] To address the significant slowdown in dissolution rate after accelerated dissolution and long-term stability testing of existing temozolomide formulations, the inventors explored different preparation processes. For example, they optimized premixing and final mixing parameters (time, rotation speed, etc.). Studies showed that shortening the final mixing time helps increase dissolution stability, but results in poor batch-to-batch dissolution uniformity. This invention first mixes stearic acid with other excipients, then adds temozolomide to the excipient mixture for final mixing, followed by capsule filling. The final product exhibits good dissolution performance and stability; even after 6 months of accelerated dissolution testing, the dissolution rate remains above 85% at 15 minutes, meeting the product quality standard dissolution limit requirements. The principle behind this invention is that stearic acid, being a waxy substance with hydrophobic properties, encapsulates hygroscopic materials when evenly distributed, reducing their hygroscopicity. In conventional processes, stearic acid is added as a lubricant during the final mixing stage. However, it has been found that to achieve both uniform stearic acid mixing and good dissolution stability in temozolomide formulations, it is necessary to deviate from this conventional approach and mix stearic acid before the active pharmaceutical ingredient (API) and other excipients. Therefore, this invention modifies the timing of stearic acid addition and employs forced mixing in the preparation process to ensure uniform distribution of stearic acid among the excipients, thereby reducing the hygroscopicity of hygroscopic materials. This results in an overall reduction in hygroscopicity in the formulation, achieving the effect of ensuring dissolution stability while lowering the environmental humidity requirements for formulation production.

[0026] Compared with the prior art, the present invention has the following advantages:

[0027] (1) Contents variation: Compared with capsules prepared by conventional processes, the contents of capsules prepared by the method described in this invention are less prone to segregation and stratification during storage, which is more conducive to controlling the contents variation of capsules, ensuring the uniformity of the quality of the formulation products, and greatly improving the product yield.

[0028] (2) The requirement for relative humidity in the process of this invention is relaxed to below 50%.

[0029] (3) Good dissolution effect. The final product showed good dissolution stability in the 6-month accelerated stability study, and the quality difference between batches and within batches of the formulation was smaller. Attached Figure Description

[0030] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on the provided drawings without creative effort.

[0031] Figure 1 The properties of temozolomide capsules prepared for different types of stearic acid after being stored under high humidity for 30 days, from left to right: 95 type stearic acid, 70 type stearic acid, and 50 type stearic acid.

[0032] Figure 2 The stability of the dissolution curve in water for the sample in Example 1 of this invention;

[0033] Figure 3 To demonstrate the stability of the dissolution curve in water for the sample of Comparative Example 1 of this invention;

[0034] Figure 4 To demonstrate the stability of the dissolution curve in water for the sample of Comparative Example 4 of this invention;

[0035] Figure 5 This invention provides a stability test for the dissolution curve of the sample in water used in Comparative Example 5. Detailed Implementation

[0036] This invention provides a method for preparing a temozolomide formulation, comprising the following steps:

[0037] A) Add sodium carboxymethyl starch, tartaric acid, colloidal silica, and some anhydrous lactose into a forced mixer. Then, sieve the stearic acid and the remaining anhydrous lactose and add them into the mixer. Mix well.

[0038] B) Add temozolomide to a forced mixer, mix well, and fill into capsules.

[0039] In this invention, the sodium carboxymethyl starch, tartaric acid, colloidal silica, anhydrous lactose, stearic acid, and temozolomide are all commonly used raw materials in the field, and commercially available products can be used. This invention will not elaborate further on these.

[0040] In this invention, the sodium carboxymethyl starch is preferably 7 to 23 parts by weight, more preferably 10 to 20 parts, such as 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 parts, preferably within the range of any of the above values ​​as the upper or lower limit.

[0041] In this invention, the weight parts of tartaric acid are preferably 1.5 to 9 parts, more preferably 2 to 8 parts, such as 1.5 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, 4.5 parts, 5 parts, 5.5 parts, 6 parts, 6.5 parts, 7 parts, 7.5 parts, 8 parts, 8.5 parts, and 9 parts, preferably within the range of any of the above values ​​as the upper or lower limit.

[0042] In this invention, the colloidal silica is preferably 0.2 to 0.7 parts by weight, more preferably 0.3 to 0.6 parts, such as 0.2 parts, 0.3 parts, 0.4 parts, 0.5 parts, 0.6 parts, 0.7 parts, and preferably within the range of any of the above values ​​as the upper or lower limit.

[0043] In this invention, the weight parts of the anhydrous lactose are preferably 132 to 183 parts, such as 135 to 180 parts, such as 132 parts, 135 parts, 140 parts, 145 parts, 150 parts, 155 parts, 160 parts, 165 parts, 170 parts, 175 parts, 180 parts, or 183 parts, preferably within a range where any of the above values ​​is the upper or lower limit.

[0044] In this invention, the stearic acid is preferably one or more of type 50 stearic acid, type 70 stearic acid, and type 95 stearic acid, more preferably type 50 stearic acid; the weight fraction of the stearic acid is preferably 3 to 14 parts, more preferably 5 to 10 parts, such as 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts, 14 parts, preferably within the range of any of the above values ​​as the upper or lower limit.

[0045] In this invention, the weight fraction of temozolomide is preferably 5 to 250 parts, more preferably 50 to 200 parts, such as 5 parts, 10 parts, 20 parts, 30 parts, 40 parts, 50 parts, 60 parts, 70 parts, 80 parts, 90 parts, 100 parts, 110 parts, 120 parts, 130 parts, 140 parts, 150 parts, 160 parts, 170 parts, 180 parts, 190 parts, 200 parts, 210 parts, 220 parts, 230 parts, 240 parts, and 250 parts, preferably within the range of any of the above values ​​as the upper or lower limit.

[0046] In this invention, the forced mixer is a multi-functional wet mixing granulator, or a similar mixer that combines stirring and shearing functions. The main reason for using this type of mixer is that the active pharmaceutical ingredient (API) in the formulation has poor flowability and constitutes a high proportion. Using a mixer with multi-dimensional stirring and mixing capabilities as the mixing equipment leverages its ability to force mixing of materials, reducing the requirements for material flowability during formulation preparation. This results in good uniformity of mixing of raw materials and excipients, stable mixing parameters, and good process reproducibility. An unexpected discovery of this invention is that using the above method to process temozolomide formulations not only achieves good mixing but also solves the moisture ingress problem of temozolomide formulations, allowing the environmental humidity requirement to be relaxed to below 50% (within a conventional GMP production environment).

[0047] In this invention, before adding stearic acid and the remaining anhydrous lactose, the stearic acid is first sieved, and then the remaining anhydrous lactose is sieved. This is because stearic acid is a white, waxy, transparent solid or a slightly yellowish waxy solid that easily clumps. Sieving the stearic acid breaks up any clumps, making it easier to mix evenly in the mixer. Sieving with lactose then washes the sieve, removing any stearic acid residue that has accumulated on the sieve, ensuring that the proportions of each component in the formulation remain constant. This prevents significant differences in intra-batch dissolution stability of the formulation due to uneven mixing during subsequent capsule filling. In this invention, the sieve used for sieving the stearic acid is preferably 18–60 mesh, more preferably 24–40 mesh, such as 18 mesh, 24 mesh, 30 mesh, 40 mesh, or 60 mesh, preferably within the range of any of the above values ​​as the upper or lower limit.

[0048] In this invention, the stirring speed for the premixing of the auxiliary materials is preferably 200-400 rpm, more preferably 250-350 rpm, such as 200 rpm, 220 rpm, 250 rpm, 280 rpm, 300 rpm, 320 rpm, 350 rpm, 380 rpm, 400 rpm, and preferably within the range of any of the above values ​​as the upper or lower limit; the cutting speed is preferably 700-1000 rpm, more preferably 800-900 rpm, such as 700 rpm, 750 rpm, 800 rpm, 850 rpm, 900 rpm, 950 rpm, 1000 rpm, and preferably within the range of any of the above values ​​as the upper or lower limit; the mixing time is preferably 10-20 min, more preferably 12-18 min, such as 10 min, 11 min, 12 min, 13 min, 14 min, 15 min, 6 min, 17 min, 18 min, 19 min, 20 min, and preferably within the range of any of the above values ​​as the upper or lower limit.

[0049] After the excipients are premixed, temozolomide is added and the mixture is then fully mixed.

[0050] In this invention, the stirring speed of the total mixing is preferably 200-400 rpm, more preferably 250-350 rpm, such as 200 rpm, 220 rpm, 250 rpm, 280 rpm, 300 rpm, 320 rpm, 350 rpm, 380 rpm, 400 rpm, and preferably within the range of any of the above values ​​as the upper or lower limit; the cutting speed is preferably 400-600 rpm, more preferably 450-550 rpm, such as 400 rpm, 450 rpm, 500 rpm, 550 rpm, 600 rpm, and preferably within the range of any of the above values ​​as the upper or lower limit; the mixing time is preferably 3-7 min, more preferably 4-6 min, such as 4 min, 5 min, 6 min, 7 min, and preferably within the range of any of the above values ​​as the upper or lower limit.

[0051] During premixing and total mixing, when the stirring and shearing speeds are below the minimum speed, the materials are not easily mixed evenly, requiring too long a mixing time, resulting in high energy consumption and hindering cost control. When the speed exceeds the maximum speed, the materials are easily thrown onto the mixer wall and cover under the action of centrifugal force, preventing them from being fully mixed. This also increases product loss and reduces yield.

[0052] After the total mixing is completed, the resulting mixture is filled into capsules to obtain temozolomide capsule formulation.

[0053] The present invention preferably uses a tube-type capsule machine equipped with a vacuum suction groove for filling. During the filling process, the vacuum degree of the vacuum suction groove is preferably maintained at -0.3 to -0.6 bar, more preferably -0.4 to -0.5 bar.

[0054] The temozolomide total powder prepared by the process described in this invention has relatively poor flowability. Conventional metering disc capsule machines cannot solve the problem of large variations in fill weight. This invention, considering the characteristics of the total powder mixture, ultimately determines to use a cannula-type capsule filling machine for capsule filling. The fill weight variation of the prepared capsules can be controlled within ±4% of the theoretical fill weight, effectively ensuring that the content uniformity of the formulation meets the standard requirements. The combination of a vacuum suction tank and a cannula-type capsule machine is effective. When using the cannula-type capsule filling machine, the relative humidity of the environment must first be controlled below 50%. Simultaneously, a vacuum suction tank is required, and the vacuum degree must be controlled at -0.3 to -0.6 bar to expel air from the total powder mixture, reducing the possibility of powder bridging, thereby ensuring stable and controllable fill weight and the most stable capsule filling process.

[0055] The present invention also provides a temozolomide formulation, particularly a capsule formulation, prepared according to the preparation method described above.

[0056] To further illustrate the present invention, the following detailed description of a temozolomide formulation and its preparation method provided by the present invention is provided in conjunction with embodiments, but it should not be construed as limiting the scope of protection of the present invention.

[0057] The stearic acid types 50 (batch number: 20210121698), 70 (batch number: 20210507346), and 95 (batch number: 20210316192) used in the following examples or comparative examples were all manufactured by HESEGO.

[0058] The mixer used in the following embodiments or comparative examples is a multi-functional wet mixing granulator, model Mini-CG, manufactured by Chuangzhi Technology (Jiangsu) Co., Ltd. This equipment is a forced mixer. It should be noted that the process provided by this invention uses the mixing function of the multi-functional wet mixing granulator, allowing for direct powder filling without the need for granulation.

[0059] The following examples and comparative examples all use the preparation process of 100mg temozolomide capsules as an example. The same preparation process can also achieve the same effect for 5mg, 20mg and 250mg temozolomide capsules.

[0060] The following examples are used to illustrate the present invention, but are not intended to limit the scope of the invention.

[0061] Example 1:

[0062] 1. Formula: See Table 2.

[0063] Table 2: Formulation of Temozolomide Capsules (100mg)

[0064] Temozolomide 100 Anhydrous lactose 175.7 Sodium carboxymethyl starch 15.0 Colloidal silica 0.3 tartaric acid 3.0 stearic acid 6.0

[0065] 2. Preparation process:

[0066] 1) Weighing: Weigh out temozolomide, anhydrous lactose, sodium carboxymethyl starch, tartaric acid, colloidal silica, and type 50 stearic acid according to the formula, and set aside.

[0067] 2) Premixing of excipients: Add sodium carboxymethyl starch, tartaric acid, colloidal silica, and half of the anhydrous lactose in the formula to the multi-functional wet mixing granulator. Then, add type 50 stearic acid and the remaining anhydrous lactose through a 40-mesh sieve to the multi-functional wet mixing granulator. Set the stirring speed to 400 rpm and the cutter speed to 800 rpm, and mix for 15 minutes.

[0068] 3) Total mixing: Add temozolomide to the multi-functional wet mixing granulator of step 2), set the stirring speed to 300 rpm and the cutter speed to 600 rpm, and mix for 5 minutes;

[0069] 4) Capsule filling: A cannula-type capsule machine equipped with a vacuum suction groove is used to maintain the vacuum degree at -0.5 bar. The total mixture is filled into capsules to obtain the formulation.

[0070] Comparative Example 1:

[0071] Referring to the formula in 00805865.2 (publication number CN1345240A) and the preparation process in 201710633102.0 (publication number CN107397735A), the specific process is as follows:

[0072] 1. Formula: See Table 2

[0073] 2. Preparation process: The API (temozolomide) and excipients other than lubricant are mixed using a conventional hopper mixer. Then, lubricant (stearic acid) is added and mixed evenly. The mixture is then filled into capsules using a metering disc capsule filling machine to obtain the formulation.

[0074] Experiment Example 1: Critical Relative Humidity Experiment

[0075] The critical relative humidity of temozolomide capsules prepared using different processes was investigated, and the evaluation index was the moisture absorption rate of the contents at different times.

[0076] 1. Samples: Temozolomide capsules provided in Example 1 and Comparative Example 1.

[0077] Take 1g of the contents of each of the above samples and place them in weighing bottles. Place each bottle in a container with a different relative humidity (see Table 3). Take out the weighing bottles 24 hours after sample placement, weigh them accurately, and calculate the moisture absorption rate of the samples.

[0078] Table 3: Correspondence between saturated solutions of sulfuric acid and salts of different concentrations and relative humidity (25℃)

[0079] Relative humidity (%) 22 29.55 40.52 48.52 57.7 75.28 84.26 92.48

[0080] 2. Detection Method

[0081] 2.1 Moisture Absorption Rate: Weigh the sample using a balance with a strength of 0.01% and calculate the moisture absorption rate using the following formula:

[0082] Moisture absorption rate = (weight of powder after moisture absorption - weight of powder before moisture absorption) / weight of powder before moisture absorption × 100%.

[0083] 2.2 Critical Relative Humidity: Plot a moisture absorption equilibrium curve with moisture absorption rate on the vertical axis and relative humidity on the horizontal axis. The intersection of the tangents at the point of stable moisture absorption and the point of sudden increase in moisture absorption is the critical relative humidity.

[0084] 3. Test results: See Table 4

[0085] Table 4: Critical Relative Humidity Results of Temozolomide Capsule Contents

[0086]

[0087] Table 4 Results Analysis: The critical relative humidity test results show that the temozolomide capsules prepared using different processes have different moisture absorption rates within the same time period when the ambient humidity is the same. The temozolomide capsules prepared using the process of this invention (Example 1) are less prone to moisture absorption and have a higher critical relative humidity compared to those prepared using the conventional process (Comparative Example 1). Therefore, the requirements for environmental humidity control in the production process are lower, demonstrating the superiority of the process of this invention.

[0088] Examples 2 and 3:

[0089] Temozolomide capsules were prepared using different types of stearic acid.

[0090] The formulation and preparation method are the same as in Example 1, except that the stearic acid in Example 2 is type 70 and the stearic acid in Example 3 is type 95.

[0091] Experimental Example 2: Investigation of influencing factors of temozolomide capsules.

[0092] The influencing factors of temozolomide capsules prepared using different types of stearic acid were investigated, and the evaluation indicators included: properties, related substances, etc.

[0093] 1. Sample: Temozolomide capsules provided in Examples 1-3.

[0094] The contents of the above samples were placed under the influence of high temperature (40℃), high humidity (75%RH), and light (4500±500Lx) conditions, and samples were taken at 0 days, 10 days, and 30 days to investigate their properties and related substances.

[0095] 2. Detection Method

[0096] 2.1 Appearance: When observed with the naked eye, the contents of the capsule should be off-white to light pink or light brown powder.

[0097] 2.2 Detection of related substances:

[0098] Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0099] 1) Reference Standard

[0100] Main component reference standard: Temozolomide, content 99.8%.

[0101] Impurity reference standards: Impurity E, content 99.69%; Impurity B, content 99.68%; Impurity A, content 100%.

[0102] 2) Preparation of test solution: Take an appropriate amount of the fine powder of the contents of this product (approximately equivalent to 20 mg of temozolomide), place it in a 20 ml volumetric flask, add an appropriate amount of mobile phase, shake to dissolve temozolomide and dilute to the mark, shake well, filter, and take the filtrate.

[0103] 3) Preparation of system suitability solution: Take 25 ml of 0.1 mol / L hydrochloric acid solution and 25 ml of reference solution, place them in a 100 ml volumetric flask, and heat at 80 °C for 4 h.

[0104] 4) Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the packing material (ChromCore 120 C18, 4.6×150mm, 5μm) or a column with equivalent performance; methanol-0.5% acetic acid solution (volume ratio 4:96) (containing 0.94g / L 1-hexanesulfonate sodium) was used as the mobile phase; the detection wavelength was 270nm; the flow rate was 1.0ml per minute; the column temperature was 35℃; the injection plate temperature was 4℃; and the injection volume was 20μl.

[0105] 5) Washing method: isocratic washing.

[0106] 3. Test results: See Table 5.

[0107] Table 5: Experimental Results of Influencing Factors in Examples 1-3

[0108]

[0109]

[0110] Results Analysis: After 30 days of storage under high temperature and light conditions, the contents of the temozolomide capsules prepared in Examples 1-3 showed no significant change compared to day 0. After 30 days of storage under high humidity conditions, the color of the contents of the temozolomide capsules prepared in Examples 1-3 gradually deepened compared to day 0 (see...). Figure 1 It can be observed that after prolonged storage, the higher the stearic acid content (95% > 70% > 50%), the smaller the color change of the capsule contents.

[0111] Under high temperature and high humidity conditions, the growth of related substances in Examples 1 and 2 was faster than that in Example 3. The growth trend was directly related to the stearic acid type, with the growth rate being 95 type < 70 type < 50 type. However, the related substances still met the standard limit requirement of <1.5% for total impurities in temozolomide capsules in the Chinese Pharmacopoeia.

[0112] Considering economic factors and market availability, the inventors considered using type 50 stearic acid as a lubricant for further investigation.

[0113] Comparative Example 2:

[0114] The formula is the same as in Example 1.

[0115] Preparation method: The difference is that when filling the capsules, a conventional metering disc capsule filling machine is used.

[0116] 1) Weighing: Weigh temozolomide, anhydrous lactose, sodium carboxymethyl starch, tartaric acid, colloidal silica, and stearic acid according to the formula, and set aside;

[0117] 2) Premixing of excipients: Add sodium carboxymethyl starch, tartaric acid, colloidal silica, and half of the anhydrous lactose in the formula to the multi-functional wet mixing granulator. Then add stearic acid and the remaining anhydrous lactose through a 40-mesh sieve to the wet mixing granulator. Set the stirring speed to 400 rpm and the cutter speed to 800 rpm, and mix for 15 minutes.

[0118] 3) Total mixing: Add temozolomide to the multi-functional wet mixing granulator of step 2), set the stirring speed to 300 rpm and the cutter speed to 600 rpm, and mix for 5 minutes;

[0119] 4) Capsule filling: A metering disc capsule filling machine is used, equipped with a 20mm thick metering disc, to fill the total mixture into capsules to obtain the formulation.

[0120] Comparative Example 3:

[0121] The formula is the same as in Example 1.

[0122] Preparation method: The difference is that when filling the capsules, a cannula-type capsule filling machine is used, without a vacuum suction groove.

[0123] 1) Weighing: Weigh temozolomide, anhydrous lactose, sodium carboxymethyl starch, tartaric acid, colloidal silica, and stearic acid according to the formula, and set aside;

[0124] 2) Premixing of excipients: Add sodium carboxymethyl starch, tartaric acid, colloidal silica, and half of the anhydrous lactose in the formula to the multi-functional wet mixing granulator. Then add stearic acid and the remaining anhydrous lactose through a 40-mesh sieve to the wet mixing granulator. Set the stirring speed to 400 rpm and the cutter speed to 800 rpm, and mix for 15 minutes.

[0125] 3) Total mixing: Add temozolomide to the multi-functional wet mixing granulator of step 2), set the stirring speed to 300 rpm and the cutter speed to 600 rpm, and mix for 5 minutes;

[0126] 4) Capsule filling: Using a tube-type capsule filling machine, the total mixture is filled into capsules to obtain the formulation.

[0127] Experiment Example 3: Investigation of the differences in fill weight of samples with different capsule filling processes

[0128] Equipment compatibility was investigated for temozolomide capsules filled using capsule machines with different operating principles. The evaluation index was the difference in fill volume.

[0129] 1. Samples: Temozolomide capsules provided in Example 1, Comparative Examples 2 and 3.

[0130] 2. Detection Method - Fill Weight Variation Detection

[0131] The test was conducted according to the "Fill Weight Difference" test method under the General Chapter 0103 of the 2020 edition of the Chinese Pharmacopoeia, Part IV.

[0132] 3. Test results: See Table 6.

[0133] Table 6: Filling Volume Variance Inspection

[0134] Filling volume difference -1.4％～+2.8％ -5.8％～+9.6％ -4.9％～+6.1％

[0135] The results in Table 6 show that the difference in fill weight between Example 1 and Comparative Example 3, which were filled using a cannula-type capsule filling machine, was smaller than that between Comparative Example 2, which was filled using a metering disc-type capsule filling machine. The main reason is that the powder prepared by the formulation process shown in this invention has low flowability, and the metering disc-type capsule filling machine does not feed smoothly during the capsule filling process, resulting in a large difference in the fill weight of the prepared capsules.

[0136] Therefore, the cannula-type capsule filling machine is more compatible with the formulation process described in this invention, and the difference in the amount of the sample (such as in Example 1) obtained by using the cannula-type capsule filling machine with a vacuum suction groove is minimal, which is beneficial to control the amount of capsules and ensure that the quality of the formulation meets the standard requirements.

[0137] Comparative Example 4:

[0138] The formula is the same as in Example 1.

[0139] Preparation method: The conventional powder direct mixing method differs from Example 1 in that temozolomide, anhydrous lactose, sodium carboxymethyl starch, colloidal silica, and tartaric acid are premixed first, and then stearic acid is added to the above premixed materials for total mixing, followed by filling into capsules.

[0140] 1) Weighing: Weigh out temozolomide, anhydrous lactose, sodium carboxymethyl starch, tartaric acid, colloidal silica, and type 50 stearic acid according to the formula, and set aside.

[0141] 2) Premixing: Add the prescribed amounts of temozolomide, anhydrous lactose, sodium carboxymethyl starch, tartaric acid, and colloidal silica to a multi-functional wet mixing granulator, set the stirring speed to 400 rpm and the cutter speed to 800 rpm, and mix for 15 minutes.

[0142] 3) Total mixing: Add type 50 stearic acid to the multi-functional wet mixing granulator of step 2), set the stirring speed to 300 rpm and the cutter speed to 600 rpm, and mix for 5 minutes;

[0143] 4) Capsule filling: A cannula-type capsule machine equipped with a vacuum suction groove is used to maintain the vacuum degree at -0.5 bar. The total mixture is filled into capsules to obtain the formulation.

[0144] Comparative Example 5:

[0145] The formula is the same as in Example 1.

[0146] Preparation method: The difference lies in that, during premixing, stearic acid is not pretreated in any way; it is directly mixed with other excipients, specifically as follows:

[0147] 1) Weighing: Weigh temozolomide, anhydrous lactose, sodium carboxymethyl starch, tartaric acid, colloidal silica, type 50 stearic acid, and stearic acid according to the formula, and set aside.

[0148] 2) Premixing of excipients: Add type 50 stearic acid, anhydrous lactose, sodium carboxymethyl starch, tartaric acid, and colloidal silica to a multi-functional wet mixing granulator, set the stirring speed to 400 rpm and the cutter speed to 800 rpm, and mix for 15 minutes.

[0149] 3) Total mixing: Add temozolomide to the multi-functional wet mixing granulator of step 2), set the stirring speed to 300 rpm and the cutter speed to 600 rpm, and mix for 5 minutes;

[0150] 4) Capsule filling: A cannula-type capsule machine equipped with a vacuum suction groove is used to maintain the vacuum degree at -0.5 bar. The total mixture is filled into capsules to obtain the formulation.

[0151] Experiment Example 4: Stability Test

[0152] The samples prepared by the process described in this invention (Example 1), the conventional process (Comparative Example 1), the conventional feeding sequence (Comparative Example 4), and Comparative Example 5 were packaged in double aluminum blister packs and subjected to accelerated stability testing for 6 months at 40°C and 75% RH. The evaluation indicators included moisture, related substances, and dissolution curves.

[0153] 1. Samples: Formulations provided in Example 1, Comparative Example 1, Comparative Example 4, and Comparative Example 5.

[0154] 2. Detection method:

[0155] 2.1 Detection method for related substances: Same as in Experimental Example 2.

[0156] 2.2 Dissolution curve detection method:

[0157] Dissolution and release were determined according to the method of determination of dissolution and release (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method I).

[0158] 1) Dissolution conditions: Use 900ml of water as the dissolution medium, rotate at 100 revolutions per minute, and operate according to the procedure. Take samples at 5, 10, 15, and 30 minutes.

[0159] 2) Test solution: Take 10 ml of the dissolution solution, filter it, and take the filtrate.

[0160] 3) Reference solution: Take an appropriate amount of temozolomide reference standard, accurately weigh it, dissolve it in water and dilute it quantitatively to prepare a solution containing about 0.11 mg of temozolomide per 1 ml (100 mg specification).

[0161] 4) Assay: Take the test solution and the reference solution, and measure the absorbance at a wavelength of 330 nm using ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0401). Calculate the dissolution amount per particle.

[0162] 3. Test results: See Table 7.

[0163] Table 7: Results of Accelerated Stability Testing

[0164]

[0165] 4. Analysis and Discussion

[0166] The results of the accelerated stability study over 6 months showed that there was no significant difference in moisture content between the temozolomide capsules prepared by the formulation process described in this invention (Example 1), the conventional process (Comparative Example 1), Comparative Example 4, and Comparative Example 5. The moisture content was less than 1.0%, indicating that the double aluminum blister packaging method used in this invention can effectively isolate moisture in the environment. The impurity level showed an increasing trend over time, but the total impurity growth rate of the samples prepared using the material addition order described in this invention (Example 1, Comparative Example 5) was smaller than that of the conventional addition order (Comparative Example 1, Comparative Example 4), demonstrating the superiority of the material addition order described in this invention.

[0167] After a 6-month accelerated stability study, the dissolution curve of the formulation process shown in this invention (Example 1) showed no significant change compared to day 0 (see [reference]). Figure 2 The dissolution rate of samples prepared using conventional processes (Comparative Example 1) and conventional feeding sequences (Comparative Example 4) both decreased significantly over time (see [reference]). Figure 3 , Figure 4 After one month of accelerated dissolution, the dissolution rate was less than 85% at 15 minutes; the dissolution rate of the sample prepared in Comparative Example 5 fluctuated irregularly at various points (see...). Figure 5 The results showed significant batch-to-batch variations, highlighting the necessity of sieving and dispersing stearic acid before premixing.

[0168] The dissolution test data show that the temozolomide capsules prepared using the process described in this invention have better dissolution stability, demonstrating the superiority of the process.

[0169] Therefore, the temozolomide capsules prepared using the prescription and process described in this invention have good process robustness, low requirements for humidity in the formulation process environment, and better product stability. This is beneficial for improving product quality stability while ensuring patient safety, and this invention has significant practical significance.

[0170] Example 4:

[0171] The mixing conditions vary depending on the multi-functional wet mixing granulation equipment.

[0172] The formula is the same as in Table 2, the difference lies in the preparation process:

[0173] 1) Weighing: Weigh out temozolomide, anhydrous lactose, sodium carboxymethyl starch, tartaric acid, colloidal silica, and type 50 stearic acid according to the formula, and set aside.

[0174] 2) Premixing of excipients: Add half of the anhydrous lactose, sodium carboxymethyl starch, tartaric acid, and colloidal silica to the multi-functional wet mixing granulator. Then, add type 50 stearic acid and the remaining anhydrous lactose through a 40-mesh sieve to the multi-functional wet mixing granulator. Set the stirring speed to 200 rpm and the cutter speed to 700 rpm, and mix for 20 minutes.

[0175] 3) Total mixing: Add temozolomide to the multi-functional wet mixing granulator of step 2), set the stirring speed to 200 rpm and the cutter speed to 400 rpm, and mix for 7 min;

[0176] 4) Capsule filling: A cannula-type capsule machine equipped with a vacuum suction groove is used to maintain the vacuum degree at -0.5 bar. The total mixture is filled into capsules to obtain the formulation.

[0177] Example 5:

[0178] The mixing conditions vary depending on the multi-functional wet mixing granulation equipment.

[0179] The formula is the same as in Table 2, the difference lies in the preparation process:

[0180] 1) Weighing: Weigh out temozolomide, anhydrous lactose, sodium carboxymethyl starch, tartaric acid, colloidal silica, and type 50 stearic acid according to the formula, and set aside.

[0181] 2) Premixing of excipients: Add half of the anhydrous lactose, sodium carboxymethyl starch, tartaric acid, and colloidal silica to the multi-functional wet mixing granulator. Then, add type 50 stearic acid and the remaining anhydrous lactose through a 40-mesh sieve to the multi-functional wet mixing granulator. Set the stirring speed to 300 rpm and the cutter speed to 900 rpm, and mix for 12 minutes.

[0182] 3) Total mixing: Add temozolomide to the multi-functional wet mixing granulator of step 2), set the stirring speed to 400 rpm and the cutter speed to 600 rpm, and mix for 3 minutes;

[0183] 4) Capsule filling: A cannula-type capsule machine equipped with a vacuum suction groove is used to maintain the vacuum degree at -0.5 bar. The total mixture is filled into capsules to obtain the formulation.

[0184] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing a temozolomide formulation, comprising the following steps: A) Add sodium carboxymethyl starch, tartaric acid, colloidal silica, and some anhydrous lactose to a forced mixer. Then, pass stearic acid through an 18-60 mesh sieve. After washing the sieve with the remaining anhydrous lactose, add it to the mixer and mix well. The stirring speed of the forced mixer is 200-400 rpm, the cutter speed is 700-1000 rpm, and the mixing time is 10-20 min. B) Add temozolomide to a forced mixer, mix well, and fill into capsules. The stirring speed of the forced mixer is 200~400 rpm, the cutter speed is 400~600 rpm, and the mixing time is 3~7 min. The proportions of the components in the temozolomide preparation by weight are as follows: temozolomide 5-250 parts, anhydrous lactose 132-183 parts, sodium carboxymethyl starch 7-23 parts, colloidal silica 0.2-0.7 parts, tartaric acid 1.5-9 parts, and stearic acid 3-14 parts.

2. The preparation method according to claim 1, characterized in that, The stearic acid is one or more of type 50 stearic acid, type 70 stearic acid, and type 95 stearic acid.

3. The preparation method according to claim 1, characterized in that, In step A), the amount of lactose used is half to two-thirds of the total amount of lactose used.

4. The preparation method according to claim 1, characterized in that, During the preparation process, the ambient humidity requirement is ≤50%.

5. The preparation method according to claim 1, characterized in that, In step B), a cannula-type capsule machine equipped with a vacuum suction groove is used for filling, and the vacuum degree of the filling is -0.3 to -0.6 bar.

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