Preparation method for large-scale industrial production of HC-1119 soft capsules.

Abstract

DEPCT67 This invention provides a method for the production of HC-1119 soft capsules at a scale. The industry includes the following steps: (1) preparation of the capsule shell; (2) preparation of the dosage. Capacity;(3)In this invention, the pelletizing process was adjusted by adding operations. The constant state of vacuum during the preparation of the adhesive solution and its viscosity. The adhesive solution was controlled from 16,000 centipoise to 25,000 centipoise while the... The operation of the nitrogen protection mode is changed during the preparation of the capacity. The rotational speed is precisely controlled, and the device parameters are precisely controlled. During the tablet compression process, the preparation of HC-1119 soft capsules can meet the requirements. Industrial-scale production can lead to impurities in the prepared HC-1119 soft capsules. Less is more and the quality is better, which is suitable for practical production as well as distribution and Applications;

Description

A method for preparing HC-1119 soft capsules for industrial mass production Technical Field

[0001] The present invention relates to a method for industrialized mass production of HC-1119 soft capsules. Background Art

[0002] HC-1119 is an androgen receptor (AR) inhibitor that competitively inhibits the binding of androgens to the AR, blocking the AR signaling pathway. It is currently used to treat androgen signaling pathway-dependent diseases such as prostate cancer and breast cancer. HC-1119's chemical name is: 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxo-1-imidazolidinyl}-2-fluoro-N-trideuterated methylbenzamide, and its structural formula is as follows:

[0003] CN 110478347 B discloses HC-1119 soft capsules. By dissolving the HC-1119 raw material in caprylic / capric macrogol glycerides, this method significantly improves HC-1119's solubility, greatly enhancing its bioavailability, reducing inter-individual variability in blood trough concentrations and exposure, and improving drug safety. However, actual production and Phase III clinical trials revealed that the soft capsules produced by this method exhibited poor batch consistency and high impurity content, necessitating further optimization and improvement.

[0004] Summary of the Invention

[0005] In order to solve the above technical problems, the present invention provides a method for industrial large-scale production of HC-1119 soft capsules, which comprises the following steps:

[0006] (1) Capsule shell preparation:

[0007] a. Heat and stir sorbitol sorbitan solution, glycerin and purified water in a gel tank. When the solution temperature reaches 70±5℃, continue stirring for 20-30 minutes.

[0008] b. Take part of the solution obtained in step a), add titanium dioxide, disperse it with a high-speed shearing machine, pour it into a glue tank after uniform dispersion, and continue stirring for 20 to 30 minutes;

[0009] c. After the liquid in the gelatin tank is heated to 70±5℃, add gelatin into the tank and stir for 30~40min under a vacuum degree of -0.06~-0.10Mpa. After turning the material over, continue stirring for 30~40min under a vacuum degree of -0.06~-0.10Mpa. Then, maintain the vacuum degree and let it stand for 30~40min. When the viscosity of the liquid reaches 16000-25000CP, keep it at 60±5℃ under non-vacuum state for 8~72h.

[0010] (2) Preparation of contents

[0011] 1) Caprylic / capric acid macrogol glycerides were added to a batch tank, vacuumed, and then filled with nitrogen. Stirring was started and heated to a liquid temperature of 40-50° C., followed by adding butylated hydroxyanisole and butylated hydroxytoluene. The mixture was stirred at 450±50 RPM for 20±5 min, and then HC-1119 was added. The mixture was vacuumed again and filled with nitrogen. The mixture was stirred at 40-50° C. and 450±50 RPM for 70±10 min.

[0012] 2) evacuating the solution obtained in step 1) in a liquid preparation tank, filling it with nitrogen, cooling it to 15-30° C., and storing it for 1-5 days;

[0013] (3) Pill pressing

[0014] Under nitrogen protection, control the thickness of the rubber to 1.0mm-1.1mm, the filling amount of the capsule content is ±5% of the theoretical amount, the thickness of the glue seam is greater than 0.2mm, and press the capsule;

[0015] After the B capsule is pressed, it is blown to the roller by cold air to set the shape, and then dried at a temperature of 17.0-27.0°C and a humidity of 10-35% until the moisture content of the content is less than 5.0%.

[0016] Furthermore, in step a), the interlayer temperature of the glue tank is 70±5° C.; stirring is continued for 20 minutes.

[0017] Furthermore, in step b), stirring is continued for 20 minutes.

[0018] Furthermore, in step c), the mixture is stirred at a vacuum degree of -0.06 to -0.10 MPa for 30 minutes, and after turning over, the mixture is continued to be stirred at a vacuum degree of -0.06 to -0.10 MPa for 30 minutes, and then the vacuum degree is maintained and the mixture is kept still for 30 minutes; when the viscosity of the liquid is lower than 16000CP, the viscosity is increased to higher than 16000CP by stirring at a vacuum degree of -0.06 to -0.10 MPa for 5 to 20 minutes; when the viscosity of the liquid is higher than 25000CP, the viscosity is increased to lower than 25000CP by adding water and stirring at a vacuum degree of -0.06 to -0.10 MPa for 5 to 20 minutes.

[0019] Furthermore, the operation of vacuuming and then filling with nitrogen in step 1) is repeated 3 times.

[0020] Furthermore, the equipment parameters for the pelletizing are as follows: wedge temperature 43.0-49.0°C, glue spreading box temperature 55.0-65.0°C, cooling drum temperature 14.0-18.0°C, pelletizing speed 2.0-3.0RPM, drying time of each rotating cage 1800s, and reversing time of each rotating cage 120s.

[0021] Furthermore, the raw materials of the capsule shell are fed in an amount of: 180-190 parts of gelatin, 55-56 parts of glycerin, 70-80 parts of sorbitol sorbitan solution, 2-3 parts of titanium dioxide, and 151-152 parts of purified water, preferably: 180.918 parts of gelatin, 55.2 parts of glycerin, 70.196 parts of sorbitol sorbitan solution, 2.07 parts of titanium dioxide, and 151.616 parts of purified water.

[0022] Furthermore, the weight ratio of the raw materials and auxiliary materials in the content is:

[0023] 40 parts of androgen receptor inhibitor HC-1119, 958.9 parts of caprylic / capric macrogol glycerides, 1 part of butylated hydroxyanisole, and 0.1 part of butylated hydroxytoluene.

[0024] Furthermore, each HC-1119 soft capsule contains 40 mg of the androgen receptor inhibitor HC-1119.

[0025] The preparation method of HC-1119 soft capsules provided by the present invention is based on CN 110478347B. The production process is adjusted by adding a vacuum static operation during the preparation of the gelatin solution and controlling the gelatin solution viscosity to 16,000-25,000 cp. Furthermore, the nitrogen protection mode is changed during the preparation of the contents, and the rotation speed is precisely controlled. Furthermore, the equipment parameters are precisely controlled during the pelleting process. This ensures that the preparation of the HC-1119 soft capsules meets the requirements of industrial scale-up production. Furthermore, the prepared HC-1119 soft capsules have a low impurity content, better quality, and are suitable for actual production and promotion.

[0026] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0027] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. DETAILED DESCRIPTION

[0028] Example 1 HC-1119 soft capsule

[0029] formula:

[0030] Preparation method:

[0031] (1) Capsule shell preparation:

[0032] a. Raise the interlayer temperature of the glue tank to 70±5℃, take sorbitol sorbitan solution, glycerin and purified water in the glue tank, heat and stir. When the solution temperature reaches 70±5℃, continue stirring for 20 minutes;

[0033] b. Take part of the solution obtained in step a), add titanium dioxide, disperse it with a high-speed shearing machine, pour it into a glue tank after uniform dispersion, and continue stirring for 20 minutes;

[0034] c. After the temperature of the liquid in the gelatin tank rises to 70±5℃, add gelatin into the tank and stir for 30 minutes under a vacuum degree of -0.06~-0.10Mpa. After turning over, continue stirring for 30 minutes under a vacuum degree of -0.06~-0.10Mpa. Then maintain the vacuum degree and let it stand for 30 minutes. When the viscosity of the liquid reaches 16000-25000CP, keep it at 60±5℃ under non-vacuum state for 8~72h. If the viscosity of the liquid is lower than 16000CP, stir it for 5~20 minutes under a vacuum degree of -0.06~-0.10Mpa to make it higher than 16000CP. If the viscosity of the liquid is higher than 25000CP, add water and stir it for 5~20 minutes under a vacuum degree of -0.06~-0.10Mpa to make it lower than 25000CP.

[0035] (2) Preparation of contents

[0036] 1) Caprylic / capric acid macrogol glycerides were added to a batch tank, and the mixture was vacuumed three times and then filled with nitrogen. Stirring was started and the mixture was heated to a liquid temperature of 40-50°C. Then, butylated hydroxyanisole and butylated hydroxytoluene were added. The mixture was stirred at 450±50 RPM for 20±5 minutes, and then HC-1119 was added. The mixture was vacuumed again and then filled with nitrogen. This was repeated three times. The mixture was stirred at 40-50°C and 450±50 RPM for 70±10 minutes.

[0037] 2) evacuating the solution obtained in step 1) in a liquid preparation tank, filling it with nitrogen, cooling it to 15-30° C., and storing it for 1-5 days;

[0038] (3) Pill pressing

[0039] Under nitrogen protection, control the thickness of the rubber to 1.0mm-1.1mm, the filling amount of the capsule content is ±5% of the theoretical amount, the thickness of the glue seam is greater than 0.2mm, and press the capsule;

[0040] After the B capsule is pressed, it is blown to the roller by cold air to set the shape, and then dried at a temperature of 17.0-27.0℃ and a humidity of 10-35% until the moisture content of the content is less than 5.0%.

[0041] The equipment parameters for pelletizing are as follows: wedge temperature 43.0-49.0°C, glue spreading box temperature 55.0-65.0°C, cooling drum temperature 14.0-18.0°C, pelletizing speed 2.0-3.0RPM, drying time of each section of the tumbler 1800s, and reversing time of each section of the tumbler 120s.

[0042] The beneficial effects of the present invention are further illustrated by the following test examples:

[0043] Experimental Example 1 Study on the Preparation Process of HC-1119 Soft Capsules

[0044] 1. Recipe:

[0045] Table 1 HC-1119 soft capsule formula composition

[0046] Remark:

[0047] [1]: “w / w” means by weight.

[0048] [2]: Calculate the API dosage based on the API COA: API dosage = API prescription quantity / API content (1-water content); if the HC-1119 content exceeds 100.0%, the dosage needs to be calculated based on 100.0%.

[0049] [3]: “N / A” means not applicable.

[0050] [4]: The purified water in the gelatin formulation is removed during the soft capsule drying process.

[0051] [5]: The capsule shell weight is the average weight of the capsule shells of the registered batch samples.

[0052] [6]: Light liquid paraffin is used as a lubricant in the pelletizing process and is removed in the post-processing polishing process.

[0053] [7]: Nitrogen is used as a protective gas during the preparation of the contents.

[0054] 2. Preparation process

[0055] (1) Capsule shell preparation

[0056] ① Weigh sorbitol sorbitan solution, glycerin, gelatin, and titanium dioxide according to the prescribed amount;

[0057] ② Heat the interlayer of the glue tank to 70±5℃. Add sorbitol sorbitan solution, glycerin and purified water, start stirring and heat the mixed solution to 70±5℃. When the temperature of the mixed solution reaches 70±5℃, continue stirring for 20 minutes to mix it evenly.

[0058] ③ Release some of the mixed solution from the glue tank, add titanium dioxide to the solution, use a shearing machine to shear and disperse it, and pour it into the glue tank after it is evenly dispersed. Stir for about 20 minutes to ensure uniform dispersion;

[0059] ④ After the liquid in the gel tank is heated to 70±5℃, add gelatin to the tank, start stirring, start vacuum degassing, maintain the vacuum degree at -0.06~-0.10Mpa and stir for 30 minutes, then stop stirring, release about 20kg of sol and turn the material over, then restart the vacuum pump and stirring, maintain the vacuum degree at -0.06~-0.10Mpa, and continue stirring for 30 minutes.

[0060] ⑤Continue to maintain the vacuum degree at -0.06~-0.10Mpa for 30 minutes;

[0061] ⑥ Turn off the vacuum and fill the glue tank with air to relieve the pressure.

[0062] ⑦ Take samples and measure the viscosity of the sol. The viscosity range is 16,000~25,000CP.

[0063] ⑧If the viscosity is lower than the lower limit or if bubbles or particles are found in the sample, continue stirring and apply vacuum for 5 to 20 minutes (-0.06 to -0.10 MPa), then retest the viscosity.

[0064] 9. If the viscosity exceeds the upper limit, add no more than 20 kg of purified water to the sol, continue stirring, and apply vacuum for 5 to 20 minutes (-0.06 to -0.10 MPa). Then retest the viscosity.

[0065] ⑩ The glue solution is kept warm at 60±5℃ in the glue tank for use. The insulation time is not less than 8 hours and the storage time is not longer than 72 hours.

[0066] (2) Preparation of contents

[0067] ① Weigh HC-1119 (Denlutamide), caprylic / capric macrogol glycerides, butylated hydroxyanisole, and butylated hydroxytoluene according to batch size;

[0068] ② The following operations are all nitrogen-filled, add the prescribed amount of caprylic acid capric acid macrogol glyceride to the liquid preparation tank, and start stirring. Vacuum for 5 minutes and replace with nitrogen, repeat 3 times, turn on the heating, add butylated hydroxyanisole and dibutylhydroxytoluene after the liquid temperature rises to 40-50°C, and stir at 450±50RPM for 20±5 minutes to dissolve. Add dextromethorphan into the liquid preparation tank, vacuum for 5 minutes and replace with nitrogen, repeat 3 times, the temperature is 40-50°C, and stir at 450±50RPM for 70±10 minutes to dissolve;

[0069] ③ Open the bottom valve of the liquid dispensing tank, release some of the contents, and then pour the contents back into the liquid dispensing tank. Vacuum for 5 minutes, replace with nitrogen 3 times, and stir for 5 to 15 minutes.

[0070] ④ Turn on the vacuum and maintain the vacuum between -0.06 and -0.10 MPa for 5 to 30 minutes. Turn off the vacuum and fill with nitrogen to relieve the pressure.

[0071] ⑤ Stop heating, turn on the cooling water, and when the temperature of the contents is between 15 and 30°C, stop stirring and take samples for testing.

[0072] ⑥ After weighing, fill with nitrogen for 2 to 3 minutes, label and seal for storage. The shelf life is 5 days after the production date of the contents.

[0073] (3) Pill pressing

[0074] ①Calculate the theoretical filling volume of the pressed pills based on the content determination.

[0075] Filling quantity = specification / content of main drug

[0076] Filling range: Filling amount ± 5.0%

[0077] ② The contents are conveyed into the hopper through a 200-mesh filter and filled with nitrogen for protection. When discharging the rubber, adjust the thickness of the rubber to 1.0-1.1mm, and adjust the loading amount and the spray body.

[0078] Temperature, equipment speed;

[0079] ③After the process parameters are stable, start pressing the pellets. Further adjust the parameters until the capsules are symmetrical, there is no oil leakage, the rubber thickness should be controlled within 1.0-1.1mm, the filling volume difference should be controlled within ±5%, and the glue seam thickness should be greater than 0.2mm.

[0080] ④After the capsules are pressed, they are blown to the roller by cold air to fix their shape.

[0081] (4) Drying

[0082] After the capsules are shaped, they are placed on trays and transferred to a drying tunnel for drying. Drying conditions are: temperature 17°C to 27°C, relative humidity 10% to 35%. Drying is stopped when the moisture content is less than 5.0%.

[0083] (V) Post-processing

[0084] ① Initial inspection: The initial inspection personnel will remove capsules that do not meet the appearance requirements, such as capsules with oil leakage, adhesion, indentation, or different heads, and keep capsules that meet the appearance requirements;

[0085] ②Polishing: transfer the soft capsules that have passed the initial inspection into the polishing pot for polishing;

[0086] ③ Picking: transfer the soft capsules into the hopper of the sorting machine, carry out the picking process, and collect the soft capsules of qualified size;

[0087] ④ Final inspection: The final inspection personnel check whether there are foreign objects, oil leakage, abnormal shape, color difference or other unqualified problems, use metal detectors and visual sorting machines to further sort and remove unqualified capsules.

[0088] (6) Inner packaging

[0089] Use polytrifluoroethylene / polyvinyl chloride solid pharmaceutical composite hard sheets and pharmaceutical aluminum foil for blister packaging. Qualified blister sheets are packaged in polyester / aluminum / polyethylene pharmaceutical composite bags, with 2 aluminum-plastic panels per bag.

[0090] 3. Comparison of the preparation process parameters of the present invention and CN 110478347 B

[0091] Table 2 Process comparison between the original patent sample and the present invention sample

[0092] 4. Quality comparison before and after the change

[0093] Table 3 Comparison of batch quality before and after process change

[0094] From the above results, it can be seen that only after the process parameters are optimized can they meet the needs of industrial scale-up production and make the product quality better and more stable.

[0095] In summary, the present invention optimizes the production process so that the preparation of HC-1119 soft capsules can meet the needs of industrial scale-up production. At the same time, the prepared HC-1119 soft capsules have a low impurity content and better quality, making them suitable for actual production, promotion and application.

Claims

DEPCT671. Method for the industrial production of soft capsules HC-1119, which consists of the following steps: (1) Preparation of the capsule shell: a) A solution of sorbitol, sorbitan, glycerol and purified water is added to the feeder and then heated under stirring. When the temperature of the solution reaches 70 ± 5 °C, the solution is stirred for another 20-30 minutes: b) A portion of the solution obtained in step a) is added to titanium dioxide and then the resulting solution is dispersed by high-speed shear force. After being evenly dispersed, the solution is poured into the feeder and stirred for another 20-30 minutes: c) After the solution in the feeder is heated to 70 ± 5 °C, gelatin is added to the tank and then the solution is stirred for 30-40 minutes under vacuum at -0.06 MPa to -0.10 MPa and after rotation the solution is stirred for another 30-40 minutes under vacuum at -0.06 MPa to -0.10 MPa.10 MPa followed by resting under vacuum for 30-40 minutes, the viscosity of the solution was measured at 16000-25000 centipoise and the solution was set aside to rest at 60 ± 5 °C under non-vacuum conditions for 8-72 hours to obtain the capsule shell material;(2) Preparation of the volumetric 1) Labrasol was added to another feeder tank and then the tank was vacuumed and filled with nitrogen, the stirrer was turned on and the solution was heated to a temperature of 40-50 °C, on which butyl-lated hydroxyanisol and dib The ethyl hydroxytoluene mixture was stirred at 450 ± 50 rpm for 20 ± 5 minutes and then HC-1119 was added. The tank was further vacuumed, filled with nitrogen and stirred at 40-50°C at 450 ± 50 rpm for 70 ± 10 minutes. 2) The tank containing the solution obtained in step 1) was vacuumed, filled with nitrogen, cooled to 15-30°C and kept for 1-5 days to obtain the required volume. (3) Pelletizing A) Under nitrogen protection, the capsule wall thickness was controlled to 1.0 mm - 1.

1. The filling quantity of the capsule is plus or minus 5% of the theoretical filling quantity, and the thickness of the capsule wall connection is more than 0.2 mm in order to extrude the capsules: B) After the completion of extrusion, the capsules are blown to the rollers with cold air, shaped, and dried at 17.0-27.0 degrees Celsius under a moisture content of 10-35% until the moisture content of the capsule is less than 5.0% to obtain soft capsules.

2. The method according to claim 1, which has the special characteristic that in step a) the temperature between stages of the feeding hopper is 70 plus or minus 5 degrees Celsius; further stirring is kept at 3. The method according to claim 1, which has the following characteristics: in step b), additional stirring is maintained for 20 minutes.

4. The method according to claim 1, which has the following characteristics: in step c), stirring at a vacuum of -0.06 MPa to -0.10 MPa is maintained for 30 minutes, and after rotation, stirring at a vacuum of -0.06 MPa to -0.10 MPa is maintained for 30 minutes, and then rested at a vacuum level that is maintained for 30 minutes; when the viscosity of the solution is below 16000 centipoise, the solution is stirred at a vacuum of -0.06 MPa to -0.10 MPa.10 MPa for 5-20 minutes to increase viscosity to above 16000 centipoise; when the viscosity of the solution is higher than 25000 centipoise, water is added and then the solution is stirred at a vacuum level of -0.06 MPa to -0.10 MPa for 5-20 minutes to reduce the viscosity to below 25000 centipoise.

5. The method according to claim 1, which is characterized by the operation of vacuuming and nitrogen gas filling in step 1), was repeated three times.

6. The method according to claim 1, which is characterized by the equipment parameters during pelleting is: 43.0-49.0 degrees Celsius. For wedges, 55.0-65.0°C; for the distribution box, 14.0-18.0°C; for the cooling tank, 2.0-3.0 rpm for rotation speed; drying time 1800 seconds for each rotating cage; and rewind time 120 seconds for each rotating cage.

7. The method according to claim 1, which is characterized by the feeding amount of raw materials for the capsule shell, is: 180-190 parts of gelatin, 55-56 parts of glycerol, 70-80 parts of sorbitol / sorbitan solution, 2-3 parts of titanium dioxide, and 151-152 parts of purified water. The recommended selection is 180-918 parts of gelatin, 55...2 parts glycerol, 70.196 parts sorbitol / sorbitan solution, 2.07 parts titanium dioxide, and 151.616 parts purified water.

8. Method according to patent 1, characterized by the weight ratio of raw materials and excipients in the capacity is: 40 parts androgen receptor inhibitor HC1119, 958.9 parts labrasol, 1 part butyl-lated hydroxyanisol, and 0.1 part dibutyl hydroxytoluene.

9. Any one of the methods according to patents 1-8, characterized by each HC1119 soft capsule containing 40 mg of the androgen receptor inhibitor HC1119;