Palonosetron hydrochloride soft capsule and preparation method thereof

Abstract

The invention relates to the technical field of medicine, in particular to a palonosetron hydrochloride soft capsule and a preparation method thereof.According to the palonosetron hydrochloride soft capsule and the preparation method thereof, malic acid is used for modifying gelatin, the formed malic acid esterification modified gelatin can effectively prevent condensation reaction of carboxyl and amino in the gelatin, and slow disintegration of the palonosetron hydrochloride soft capsule is reduced; through mutual cooperation of the selenized glucan and the malic acid esterification modified gelatin, the stability of the glue solution for the soft capsule shell is enhanced, the disintegration time limit of the soft capsule shell is shortened, and rapid dissolution of the palonosetron hydrochloride component in the palonosetron hydrochloride soft capsule is promoted; the palonosetron hydrochloride solution and the oil-phase composition are homogenized and emulsified at a high speed, so that the dispersity and the stability of the active ingredient of the palonosetron hydrochloride in the soft capsule content can be improved, and further rapid dissolution of the active ingredient of the palonosetron hydrochloride after the palonosetron hydrochloride soft capsule is disintegrated is facilitated.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and more specifically, to a palonosetron hydrochloride soft capsule and a preparation method thereof. Background Art

[0002] Palonosetron hydrochloride soft capsule is a pharmaceutical preparation, the main ingredient of which is palonosetron hydrochloride, which is a 5-HT3 receptor antagonist. This drug is mainly used to prevent and treat nausea and vomiting caused by chemotherapy, as well as nausea and vomiting after surgery. The raw materials of palonosetron hydrochloride soft capsule include palonosetron hydrochloride and a variety of excipients, such as oil phase matrix, antioxidants, surfactants, plasticizers and excipients. Among them, the shell of the palonosetron hydrochloride soft capsule prepared with gelatin as the main excipient material is soluble in water and gastrointestinal fluid. When the palonosetron hydrochloride soft capsule is swallowed, the shell of the palonosetron hydrochloride soft capsule quickly dissolves or breaks in the gastrointestinal tract, thereby allowing the palonosetron hydrochloride to enter the body from the liquid core to achieve the purpose of treatment.

[0003] However, the existing Palonosetron Hydrochloride Soft Capsules have problems such as poor stability of gelatin components, poor antioxidant properties, and poor storage and dispersion stability of Palonosetron Hydrochloride during actual storage, which can easily lead to oxidative degradation or failure of Palonosetron Hydrochloride in the Palonosetron Hydrochloride Soft Capsules during storage, thereby affecting the dissolution rate and efficacy of Palonosetron Hydrochloride after taking the Palonosetron Hydrochloride Soft Capsules. In addition, in the Palonosetron Hydrochloride Soft Capsules shell, the carboxyl groups in the gelatin molecules easily undergo condensation reactions with the amino groups to form crosslinks, so that a layer of membranous material that can only swell but not dissolve appears on the inner wall of the Palonosetron Hydrochloride Soft Capsules shell, affecting the dissolution effect of the gelatin molecules, affecting the disintegration of the Palonosetron Hydrochloride Soft Capsules, causing the Palonosetron Hydrochloride Soft Capsules shell to disintegrate slowly, further reducing the dissolution rate of Palonosetron Hydrochloride, and affecting the efficacy. Summary of the invention

[0004] In view of the deficiencies in the prior art, the present invention provides a palonosetron hydrochloride soft capsule and a preparation method thereof.

[0005] A method for preparing palonosetron hydrochloride soft capsules comprises the following steps: S1: Preparation of malic acid esterified modified gelatin, mixing gelatin, distilled water, malic acid and a catalyst, heating for reaction to obtain a modified gelatin solution, pouring the modified gelatin solution into an ethanol solution to form a precipitate, filtering and collecting the precipitate, washing the precipitate with an ethanol solution and vacuum drying to obtain malic acid esterified modified gelatin; S2: Preparation of glue for soft capsule shell, selenization modification of dextran to obtain selenized dextran, stirring and mixing malic acid esterified modified gelatin, distilled water, selenized dextran and plasticizer, vacuum degassing, filtering and heat preservation to obtain glue for soft capsule shell; S3: Preparation of soft capsule contents: mixing palonosetron hydrochloride with distilled water to obtain a palonosetron hydrochloride solution, stirring and mixing caprylic acid capric acid mono- and diglycerides, polyglycerol oleate and butylated hydroxyanisole to obtain an oil phase composition, stirring and mixing the palonosetron hydrochloride solution and the oil phase composition under a nitrogen atmosphere, and subjecting to high-speed shearing to obtain soft capsule contents; S4: Preparation of palonosetron hydrochloride soft capsules, rotationally molding a soft capsule shell with a glue liquid to obtain a soft capsule shell, injecting the soft capsule content into the soft capsule shell, and then sealing the filled soft capsule shell to obtain a palonosetron hydrochloride soft capsule, each palonosetron hydrochloride soft capsule containing 0.25 or 0.5 mg of palonosetron hydrochloride.

[0006] Furthermore, step S1: preparation of malic acid esterified modified gelatin specifically comprises the following steps: S1.1: Mix gelatin and distilled water, stir and dissolve at 50-60°C to prepare a gelatin solution with a mass fraction of 5-8%; S1.2: Add malic acid to the gelatin solution in an amount of 3 to 10% of the mass of the gelatin solution, stir for 10 to 20 minutes, then add a catalyst to the gelatin solution in an amount of 1 to 5% of the mass of the gelatin solution, continue stirring at 45 to 60°C for 1 to 3 hours to obtain a modified gelatin solution; S1.3: Pour the modified gelatin solution into an ethanol solution at a temperature of 10 to 15°C, slowly stir to form a precipitate, collect the precipitate by filtration, and then wash the precipitate with an ethanol solution for 2 to 4 times to remove excess malic acid and catalyst; S1.4: The washed precipitate is placed in a vacuum drying oven for vacuum drying to obtain malic acid esterified modified gelatin.

[0007] Furthermore, in step S1.2, the catalyst is 4-dimethylaminopyridine or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.

[0008] Further, step S2: preparation of the glue solution for the soft capsule shell specifically comprises the following steps: S2.1: Add dextran to a 0.5% dilute nitric acid solution, wherein the amount of dextran added is 10-20 mg / mL, stir evenly, then add sodium selenite, stir well to obtain a mixed solution, add barium chloride to the mixed solution, and the amount of barium chloride added is 0.3-0.8 g / mL; S2.2: The mixed solution with barium chloride added is transferred to a microwave digestion instrument, and reacted for 20 to 40 minutes at a microwave power of 250 to 300 W and a temperature of 50 to 60°C. After the reaction is completed, the pH of the mixed solution is adjusted to neutral with a sodium hydroxide solution having a concentration of 0.1 mol / L, and then a sodium sulfate solution having a concentration of 1 mol / L is added until the white precipitate no longer increases, and then the addition of the sodium sulfate solution is stopped, and the mixture is allowed to stand for 10 to 15 minutes. After filtering, centrifugation and taking the supernatant, the supernatant is poured into a dialysis bag and dialyzed for 2 to 4 days. Subsequently, the solution obtained after dialysis is freeze-dried to obtain selenized dextran; S2.3: Add malic acid esterified modified gelatin to distilled water at 50-65°C, stir until the malic acid esterified modified gelatin is completely dissolved, add selenized dextran, stir and mix evenly, then add plasticizer, continue to stir evenly, then vacuum degas, filter and keep warm at 50-60°C to obtain the glue solution for soft capsule shell.

[0009] Furthermore, in step S2.1, the mass ratio of sodium selenite to dextran in the mixed solution is (1-1.3):1.

[0010] Furthermore, in step S2.3, the plasticizer is at least one of glycerol and sorbitol.

[0011] Furthermore, in step S2.3, the mass ratio of malic acid esterified modified gelatin, selenylated dextran, plasticizer and distilled water is (10-30): (1-10): (4-8): (50-90).

[0012] Further, step S3: preparation of soft capsule contents, specifically comprising the following steps: S3.1: Add palonosetron hydrochloride to distilled water, stir until the palonosetron hydrochloride is completely dissolved, then add glycerol, stir and mix evenly to obtain a palonosetron hydrochloride solution, wherein the mixing mass ratio of palonosetron hydrochloride, distilled water and glycerol is (0.25-0.5):(3-5):(1-5); S3.2: Stir and mix caprylic acid capric acid mono- and diglycerides, polyglycerol oleate and butylated hydroxyanisole in a mass ratio of (100-120): (1-3): (0.1-0.5) to obtain an oil phase composition; S3.3: Under a nitrogen atmosphere, the palonosetron hydrochloride solution and the oil phase composition are stirred and mixed in a mass ratio of (1-2): (10-15) to obtain a mixed solution. Subsequently, the mixed solution is subjected to high-speed shearing by a high-speed shearing emulsifier under a nitrogen atmosphere at a shearing speed of 15000-22000 rpm and a shearing time of 3-5 min to obtain the contents of the soft capsule.

[0013] A palonosetron hydrochloride soft capsule is prepared by the preparation method of the palonosetron hydrochloride soft capsule.

[0014] The present invention has the following advantages: 1. In the present invention, malic acid can modify gelatin under the action of a catalyst, so that the carboxyl group in the malic acid and the amino group in the gelatin undergo an esterification reaction to generate a stable ester bond. The formed malic acid esterified modified gelatin can reduce the content of free amino groups in gelatin, effectively prevent the condensation reaction of the carboxyl group and the amino group in the gelatin, reduce the cross-linking sites of gelatin, and thus reduce the cross-linking phenomenon of the gelatin soft capsule, enhance the stability of the soft capsule shell, delay the aging of the gelatin component in the soft capsule shell, and reduce the occurrence of slow disintegration and dissolution of the palonosetron hydrochloride soft capsule.

[0015] 2. In the present invention, a glue solution for a soft capsule shell is prepared by mixing selenium-containing dextran, malic acid esterified modified gelatin and a plasticizer. The selenium in the selenium-containing dextran can enhance the antioxidant properties of dextran, thereby assisting in improving the antioxidant properties of the glue solution for the soft capsule shell, ensuring the overall storage stability of the palonosetron hydrochloride soft capsules, and avoiding the deterioration or failure of the palonosetron hydrochloride during storage. In addition, in the glue solution for the soft capsule shell, the selenium-containing dextran and the malic acid esterified modified gelatin form a composite structure through hydrogen bonding and electrostatic attraction. The selenium-containing dextran and the malic acid esterified modified gelatin work together to further enhance the stability of the glue solution for the soft capsule shell, while improving the solubility of the glue solution for the soft capsule shell, which is beneficial to shortening the disintegration time of the soft capsule shell and promoting the palonosetron hydrochloride component in the soft capsule to quickly exert its efficacy.

[0016] 3. In the present invention, by subjecting the mixed solution of the palonosetron hydrochloride solution and the oil phase composition to high-speed homogenization and emulsification, the palonosetron hydrochloride can be evenly dispersed in the oil phase composition to form a stable emulsified system, thereby improving the dispersibility and stability of the palonosetron hydrochloride active ingredient in the palonosetron hydrochloride soft capsules, which is beneficial to the rapid dissolution and utilization of the palonosetron hydrochloride active ingredient after the disintegration of the palonosetron hydrochloride soft capsules. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 The present invention is a flow chart of the preparation method of palonosetron hydrochloride soft capsules.

[0018] Figure 2 The figure is a quality test result diagram of the palonosetron hydrochloride soft capsules of the embodiments and comparative examples of the present invention after accelerated testing.

[0019] Figure 3 This is a graph showing the dissolution test results of the palonosetron hydrochloride soft capsules of the embodiments and comparative examples of the present invention after accelerated testing. DETAILED DESCRIPTION

[0020] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. Example 1

[0021] A method for preparing palonosetron hydrochloride soft capsules, Figure 1 As shown, the specific steps include: S1: Preparation of malic acid esterified modified gelatin, S1.1: Mix gelatin and distilled water, stir and dissolve at 60°C to prepare a gelatin solution with a mass fraction of 8%; S1.2: Add malic acid to the gelatin solution in an amount of 10% of the mass of the gelatin solution. After stirring for 20 minutes, add 4-dimethylaminopyridine to the gelatin solution in an amount of 5% of the mass of the gelatin solution. Continue stirring and reacting at 60°C for 3 hours to obtain a modified gelatin solution. S1.3: Pour the modified gelatin solution into an ethanol solution at a temperature of 12°C, slowly stir to form a precipitate, collect the precipitate by filtration, and then wash the precipitate with an ethanol solution for 4 times to remove excess malic acid and 4-dimethylaminopyridine; S1.4: placing the washed precipitate in a vacuum drying oven to dry, thereby obtaining malic acid esterified modified gelatin; S2: Preparation of glue for soft capsule shell, S2.1: Add dextran to a 0.5% dilute nitric acid solution, wherein the amount of dextran added is 20 mg / mL, stir evenly, then add sodium selenite, stir well to obtain a mixed solution, wherein the mass ratio of sodium selenite to dextran is 1:1, add barium chloride to the mixed solution, and the amount of barium chloride added is 0.7 g / mL; S2.2: The mixed solution with barium chloride added was transferred to a microwave digestion instrument, and reacted for 30 minutes at a microwave power of 300 W and a temperature of 60°C. After the reaction, the pH of the mixed solution was adjusted to neutral with a 0.1 mol / L sodium hydroxide solution, and then a 1 mol / L sodium sulfate solution was added until the white precipitate no longer increased, and then the addition of the sodium sulfate solution was stopped. The mixture was allowed to stand for 15 minutes, filtered, centrifuged, and the supernatant was taken. The supernatant was poured into a dialysis bag and dialyzed for 3 days. Subsequently, the solution obtained after dialysis was freeze-dried to obtain selenized dextran; S2.3: At 65°C, add malic acid esterified modified gelatin to distilled water, stir until the malic acid esterified modified gelatin is completely dissolved, add selenized dextran, stir and mix evenly, then add glycerol, continue to stir evenly, then vacuum degas, filter and keep warm at 60°C to obtain a glue solution for soft capsule shell, wherein the mass ratio of malic acid esterified modified gelatin, selenized dextran, glycerol and distilled water is 30:9:8:90; S3: Preparation of soft capsule contents, S3.1: Add palonosetron hydrochloride to distilled water, stir until the palonosetron hydrochloride is completely dissolved, then add glycerol, stir and mix evenly to obtain a palonosetron hydrochloride solution, wherein the mixing mass ratio of palonosetron hydrochloride, distilled water and glycerol is 0.5:3:5; S3.2: Stir and mix caprylic acid capric acid mono- and diglycerides, polyglycerol oleate and butylated hydroxyanisole to obtain an oil phase composition, wherein the mixing mass ratio of caprylic acid capric acid mono- and diglycerides, polyglycerol oleate and butylated hydroxyanisole is 120:3:0.5; S3.3: Under a nitrogen atmosphere, the palonosetron hydrochloride solution and the oil phase composition were stirred and mixed at a mass ratio of 1:15 to obtain a mixed solution. Then, the mixed solution was subjected to high-speed shearing using a high-speed shear emulsifier under a nitrogen atmosphere at a shearing speed of 20,000 rpm for a shearing time of 5 min to obtain soft capsule contents; S4: Preparation of Palonosetron Hydrochloride Soft Capsules, The soft capsule shell is poured into the mold of the soft capsule machine with glue, and rotational molding is performed to obtain the soft capsule shell. The soft capsule content is injected into the soft capsule shell through the filling device of the soft capsule machine. Subsequently, the filled soft capsule shell is sealed to obtain the palonosetron hydrochloride soft capsule, each of which contains 0.5 mg of palonosetron hydrochloride. Example 2

[0022] A method for preparing palonosetron hydrochloride soft capsules, Figure 1 As shown, the specific steps include: S1: Preparation of malic acid esterified modified gelatin, S1.1: Mix gelatin and distilled water, stir and dissolve at 50°C to prepare a gelatin solution with a mass fraction of 8%; S1.2: Add malic acid to the gelatin solution in an amount of 10% of the mass of the gelatin solution. After stirring for 10 minutes, add 4-dimethylaminopyridine to the gelatin solution in an amount of 5% of the mass of the gelatin solution. Continue stirring and reacting at 45°C for 1 hour to obtain a modified gelatin solution. S1.3: Pour the modified gelatin solution into an ethanol solution at a temperature of 12°C, slowly stir to form a precipitate, collect the precipitate by filtration, and then wash the precipitate twice with an ethanol solution to remove excess malic acid and 4-dimethylaminopyridine; S1.4: placing the washed precipitate in a vacuum drying oven to dry, thereby obtaining malic acid esterified modified gelatin; S2: Preparation of glue for soft capsule shell, S2.1: Add dextran to a 0.5% dilute nitric acid solution, wherein the amount of dextran added is 20 mg / mL, stir evenly, then add sodium selenite, stir well to obtain a mixed solution, wherein the mass ratio of sodium selenite to dextran is 1:1, add barium chloride to the mixed solution, and the amount of barium chloride added is 0.7 g / mL; S2.2: The mixed solution with barium chloride added was transferred to a microwave digestion instrument, and reacted for 40 minutes under the conditions of microwave power of 250W and temperature of 50°C. After the reaction, the pH of the mixed solution was adjusted to neutral with a sodium hydroxide solution with a concentration of 0.1mol / L, and then a sodium sulfate solution with a concentration of 1mol / L was added until the white precipitate no longer increased, and then the addition of sodium sulfate solution was stopped. The mixture was allowed to stand for 10 minutes, filtered, centrifuged and the supernatant was taken, and the supernatant was poured into a dialysis bag for 3 days of dialysis. Subsequently, the solution obtained after dialysis was freeze-dried to obtain selenized dextran; S2.3: At 60°C, add malic acid esterified modified gelatin to distilled water, stir until malic acid esterified modified gelatin is completely dissolved, add selenized dextran, stir and mix evenly, then add glycerol, continue to stir evenly, then vacuum degas, filter and keep warm at 50°C to obtain a glue solution for soft capsule shell, wherein the mass ratio of malic acid esterified modified gelatin, selenized dextran, glycerol and distilled water is 30:9:8:90; S3: Preparation of soft capsule contents, S3.1: Add palonosetron hydrochloride to distilled water, stir until the palonosetron hydrochloride is completely dissolved, then add glycerol, stir and mix evenly to obtain a palonosetron hydrochloride solution, wherein the mixing mass ratio of palonosetron hydrochloride, distilled water and glycerol is 0.5:3:5; S3.2: Stir and mix caprylic acid capric acid mono- and diglycerides, polyglycerol oleate and butylated hydroxyanisole to obtain an oil phase composition, wherein the mixing mass ratio of caprylic acid capric acid mono- and diglycerides, polyglycerol oleate and butylated hydroxyanisole is 120:3:0.5; S3.3: Under a nitrogen atmosphere, the palonosetron hydrochloride solution and the oil phase composition were stirred and mixed at a mass ratio of 1:15 to obtain a mixed solution. Then, the mixed solution was subjected to high-speed shearing using a high-speed shear emulsifier under a nitrogen atmosphere at a shearing speed of 22000 rpm for a shearing time of 3 min to obtain soft capsule contents; S4: Preparation of Palonosetron Hydrochloride Soft Capsules, The soft capsule shell is poured into the mold of the soft capsule machine with glue, and rotational molding is performed to obtain the soft capsule shell. The soft capsule content is injected into the soft capsule shell through the filling device of the soft capsule machine. Subsequently, the filled soft capsule shell is sealed to obtain the palonosetron hydrochloride soft capsule, each of which contains 0.5 mg of palonosetron hydrochloride. Example 3

[0023] A method for preparing palonosetron hydrochloride soft capsules, Figure 1 As shown, the specific steps include: S1: Preparation of malic acid esterified modified gelatin, S1.1: Mix gelatin and distilled water, stir and dissolve at 60°C to prepare a gelatin solution with a mass fraction of 5%; S1.2: Add malic acid to the gelatin solution in an amount of 5% by mass of the gelatin solution, stir for 20 minutes, then add 4-dimethylaminopyridine to the gelatin solution in an amount of 1% by mass of the gelatin solution, continue stirring at 60°C for 3 hours to obtain a modified gelatin solution; S1.3: Pour the modified gelatin solution into an ethanol solution at a temperature of 12°C, slowly stir to form a precipitate, collect the precipitate by filtration, and then wash the precipitate with an ethanol solution for 4 times to remove excess malic acid and 4-dimethylaminopyridine; S1.4: placing the washed precipitate in a vacuum drying oven to dry, thereby obtaining malic acid esterified modified gelatin; S2: Preparation of glue for soft capsule shell, S2.1: Add dextran to a 0.5% dilute nitric acid solution, wherein the amount of dextran added is 10 mg / mL, stir evenly, then add sodium selenite, stir well to obtain a mixed solution, wherein the mass ratio of sodium selenite to dextran is 1.3:1, and add barium chloride to the mixed solution, wherein the amount of barium chloride added is 0.3 g / mL; S2.2: The mixed solution with barium chloride added was transferred to a microwave digestion instrument, and reacted for 30 minutes at a microwave power of 300 W and a temperature of 60°C. After the reaction, the pH of the mixed solution was adjusted to neutral with a 0.1 mol / L sodium hydroxide solution, and then a 1 mol / L sodium sulfate solution was added until the white precipitate no longer increased, and then the addition of the sodium sulfate solution was stopped. The mixture was allowed to stand for 15 minutes, filtered, centrifuged, and the supernatant was taken. The supernatant was poured into a dialysis bag and dialyzed for 3 days. Subsequently, the solution obtained after dialysis was freeze-dried to obtain selenized dextran; S2.3: At 65°C, add malic acid esterified modified gelatin to distilled water, stir until the malic acid esterified modified gelatin is completely dissolved, add selenized dextran, stir and mix evenly, then add glycerol, continue to stir evenly, then vacuum degas, filter and keep warm at 60°C to obtain a glue solution for soft capsule shell, wherein the mass ratio of malic acid esterified modified gelatin, selenized dextran, glycerol and distilled water is 10:1:4:50; S3: Preparation of soft capsule contents, S3.1: Add palonosetron hydrochloride to distilled water, stir until the palonosetron hydrochloride is completely dissolved, then add glycerol, stir and mix evenly to obtain a palonosetron hydrochloride solution, wherein the mixing mass ratio of palonosetron hydrochloride, distilled water and glycerol is 0.25:3:1; S3.2: Stir and mix caprylic acid capric acid mono- and diglycerides, polyglycerol oleate and butylated hydroxyanisole to obtain an oil phase composition, wherein the mixing mass ratio of caprylic acid capric acid mono- and diglycerides, polyglycerol oleate and butylated hydroxyanisole is 100:1:0.1; S3.3: Under a nitrogen atmosphere, the palonosetron hydrochloride solution and the oil phase composition were stirred and mixed at a mass ratio of 1:10 to obtain a mixed solution. Then, the mixed solution was subjected to high-speed shearing using a high-speed shear emulsifier under a nitrogen atmosphere at a shearing speed of 20,000 rpm for a shearing time of 5 min to obtain soft capsule contents; S4: Preparation of Palonosetron Hydrochloride Soft Capsules, The soft capsule shell is poured into the mold of the soft capsule machine with glue, and rotational molding is performed to obtain the soft capsule shell. The soft capsule content is injected into the soft capsule shell through the filling device of the soft capsule machine. Subsequently, the filled soft capsule shell is sealed to obtain the palonosetron hydrochloride soft capsule, each of which contains 0.5 mg of palonosetron hydrochloride.

[0024] Comparative Example 1 Compared with Example 1, the difference of Comparative Example 1 is that step S1 and step S2 are removed, gelatin, distilled water and glycerol are mixed and stirred at a mass ratio of 30:8:90 at 65°C until uniform, and then vacuum degassed, filtered and kept warm at 60°C to obtain a gelatin soft capsule shell glue solution, and the soft capsule shell glue solution in step S4 is replaced with the gelatin soft capsule shell glue solution, and the other steps remain unchanged to prepare palonosetron hydrochloride soft capsules, which is recorded as Comparative Example 1.

[0025] Comparative Example 2 Compared with Example 1, the difference of Comparative Example 2 is that step S1 is removed, the malic acid esterified modified gelatin in step S2.3 is replaced with gelatin, and the other steps remain unchanged to prepare palonosetron hydrochloride soft capsules, which are recorded as Comparative Example 2.

[0026] Comparative Example 3 Compared with Example 1, the difference of Comparative Example 3 is that steps S2.1-S2.2 are removed, the step of adding selenized dextran in step S2.3 is removed, and the remaining steps remain unchanged to prepare palonosetron hydrochloride soft capsules, which is recorded as Comparative Example 3.

[0027] Comparative Example 4 Compared with Example 1, the difference of Comparative Example 4 is that the selenized dextran in step S2.3 is replaced with dextran, and the other steps remain unchanged to prepare palonosetron hydrochloride soft capsules, which is recorded as Comparative Example 4.

[0028] Comparative Example 5 Compared with Example 1, the difference of Comparative Example 5 is that the content of the soft capsule in step S4 is replaced by the mixed solution in step S3.3, and the other steps remain unchanged to prepare palonosetron hydrochloride soft capsules, which is recorded as Comparative Example 5.

[0029] Accelerated testing According to the "Guidelines for Stability Testing of APIs and Pharmaceutical Preparations" (Appendix 9001 of Part IV of the 2020 Chinese Pharmacopoeia), the stability of the palonosetron hydrochloride soft capsules of Examples 1-3 and Comparative Examples 1-5 was investigated in the accelerated test. The conditions of the accelerated test were: temperature 40°C ± 2°C, relative humidity RH75% ± 5%. Under light-proof conditions, the palonosetron hydrochloride soft capsule samples of Examples 1-3 and Comparative Examples 1-5 were placed in a constant temperature and humidity chamber for accelerated testing, and samples were taken in the 1st, 2nd, 3rd, and 6th months for quality inspection (General Rules 0512 of Part IV of the 2020 Chinese Pharmacopoeia) and dissolution test (General Rules 0931 Method 2 of Part IV of the 2020 Chinese Pharmacopoeia).

[0030] The dissolution test conditions are as follows: using 500 ml of 0.01 mol / L hydrochloric acid solution as the dissolution medium, the rotation speed is 75 revolutions per minute, and the operation is carried out in accordance with the law. The dissolution solution is taken after 5, 10 and 15 minutes, and the sampling volume of the dissolution solution is 3 mL. After filtration, the filtrate is taken as the test solution, and it is dissolved and diluted with 0.01 mol / L hydrochloric acid solution to prepare a solution containing approximately 1 μg of palonosetron per 1 ml as the reference solution, and the dissolution of each palonosetron hydrochloride soft capsule is calculated by the external standard method.

[0031] The results of quality inspection and dissolution test are as follows: Figure 2 , Figure 3 shown.

[0032] like Figure 2 It can be seen that after the accelerated test, isomers (impurity A) were detected in the palonosetron hydrochloride soft capsule samples of Comparative Examples 1 and 3 and Comparative Examples 2 and 4 at the 3rd or 6th month, respectively, while no isomers (impurity A) were detected in the palonosetron hydrochloride soft capsules of other groups after the accelerated test, indicating that the use of selenized dextran and malic acid-modified gelatin in the soft capsule shell can effectively improve the antioxidant properties of the soft capsule shell, enhance the stability of the glue for the soft capsule shell, and prevent oxidative degradation of the palonosetron hydrochloride active ingredient in the palonosetron hydrochloride soft capsule.

[0033] like Figure 3 It can be seen that during the dissolution test of the palonosetron hydrochloride soft capsules of Examples 1-3 and Comparative Examples 1-5 after the accelerated test, the palonosetron hydrochloride soft capsules of Examples 1-3 had a 5-min solubility of 11%-14%, and a 10-min solubility of 87%-91%. After 15 minutes, the palonosetron hydrochloride soft capsules were almost completely disintegrated and dissolved, achieving the purpose of rapid dissolution and onset of effect. Moreover, compared with Comparative Examples 1-5, the palonosetron hydrochloride soft capsules of Examples 1-3 had better solubility and higher dissolution efficiency. It is shown that the use of selenized dextran and malic acid esterified modified gelatin in the soft capsule shell of palonosetron hydrochloride soft capsule can effectively improve the solubility of the soft capsule shell, which is beneficial to shorten the disintegration time of the soft capsule shell, and promote the palonosetron hydrochloride component in the soft capsule to quickly exert its efficacy. In addition, compared with the mixed solution obtained by simply stirring and mixing the palonosetron hydrochloride solution and the oil phase composition, the soft capsule contents obtained by high-speed homogenization in the palonosetron hydrochloride soft capsule are more conducive to the rapid dissolution and utilization of the palonosetron hydrochloride active ingredient.

[0034] It should be understood that those skilled in the art can make improvements or changes based on the above description, and all such improvements and changes should fall within the scope of protection of the appended claims of the present invention. Parts not described in detail in this specification belong to the prior art known to those skilled in the art.

Claims

1. A method for preparing palonosetron hydrochloride soft capsules, characterized in that: The steps include: S1: Preparation of malic acid esterified modified gelatin, mixing gelatin, distilled water, malic acid and a catalyst, heating for reaction to obtain a modified gelatin solution, pouring the modified gelatin solution into an ethanol solution to form a precipitate, filtering and collecting the precipitate, washing the precipitate with an ethanol solution and vacuum drying to obtain malic acid esterified modified gelatin; S2: Preparation of glue for soft capsule shell, selenization modification of dextran to obtain selenized dextran, stirring and mixing malic acid esterified modified gelatin, distilled water, selenized dextran and plasticizer, vacuum degassing, filtering and heat preservation to obtain glue for soft capsule shell; S3: Preparation of soft capsule contents: mixing palonosetron hydrochloride with distilled water to obtain a palonosetron hydrochloride solution, stirring and mixing caprylic acid capric acid mono- and diglycerides, polyglycerol oleate and butylated hydroxyanisole to obtain an oil phase composition, stirring and mixing the palonosetron hydrochloride solution and the oil phase composition under a nitrogen atmosphere, and subjecting to high-speed shearing to obtain soft capsule contents; S4: Preparation of palonosetron hydrochloride soft capsules, rotationally molding a soft capsule shell with a glue liquid to obtain a soft capsule shell, injecting the soft capsule content into the soft capsule shell, and then sealing the filled soft capsule shell to obtain a palonosetron hydrochloride soft capsule, each palonosetron hydrochloride soft capsule containing 0.25 or 0.5 mg of palonosetron hydrochloride.

2. The method for preparing palonosetron hydrochloride soft capsules according to claim 1, wherein Step S1: Preparation of malic acid esterified modified gelatin, specifically comprising the following steps: S1.1: Mix gelatin and distilled water, stir and dissolve at 50-60°C to prepare a gelatin solution with a mass fraction of 5-8%; S1.2: Add malic acid to the gelatin solution in an amount of 3 to 10% of the mass of the gelatin solution, stir for 10 to 20 minutes, then add a catalyst to the gelatin solution in an amount of 1 to 5% of the mass of the gelatin solution, continue stirring at 45 to 60°C for 1 to 3 hours to obtain a modified gelatin solution; S1.3: Pour the modified gelatin solution into an ethanol solution at a temperature of 10 to 15°C, slowly stir to form a precipitate, collect the precipitate by filtration, and then wash the precipitate with an ethanol solution for 2 to 4 times to remove excess malic acid and catalyst; S1.4: The washed precipitate is placed in a vacuum drying oven for vacuum drying to obtain malic acid esterified modified gelatin.

3. The method for preparing the palonosetron hydrochloride soft capsule according to claim 2, wherein: In step S1.2, the catalyst is 4-dimethylaminopyridine or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.

4. The method for preparing the palonosetron hydrochloride soft capsule according to claim 3, characterized in that: Step S2: Preparation of the glue solution for the soft capsule shell, specifically comprising the following steps: S2.1: Add dextran to a 0.5% dilute nitric acid solution, wherein the amount of dextran added is 10-20 mg / mL, stir evenly, then add sodium selenite, stir well to obtain a mixed solution, add barium chloride to the mixed solution, and the amount of barium chloride added is 0.3-0.8 g / mL; S2.2: The mixed solution with barium chloride added is transferred to a microwave digestion instrument, and reacted for 20 to 40 minutes at a microwave power of 250 to 300 W and a temperature of 50 to 60°C. After the reaction is completed, the pH of the mixed solution is adjusted to neutral with a sodium hydroxide solution having a concentration of 0.1 mol / L, and then a sodium sulfate solution having a concentration of 1 mol / L is added until the white precipitate no longer increases, and then the addition of the sodium sulfate solution is stopped, and the mixture is allowed to stand for 10 to 15 minutes. After filtering, centrifugation and taking the supernatant, the supernatant is poured into a dialysis bag and dialyzed for 2 to 4 days. Subsequently, the solution obtained after dialysis is freeze-dried to obtain selenized dextran; S2.3: Add malic acid esterified modified gelatin to distilled water at 50-65°C, stir until the malic acid esterified modified gelatin is completely dissolved, add selenized dextran, stir and mix evenly, then add plasticizer, continue to stir evenly, then vacuum degas, filter and keep warm at 50-60°C to obtain the glue solution for soft capsule shell.

5. The method for preparing the palonosetron hydrochloride soft capsule according to claim 4, characterized in that: In step S2.1, the mass ratio of sodium selenite to dextran in the mixed solution is (1-1.3):

1.

6. The method for preparing the palonosetron hydrochloride soft capsule according to claim 4, characterized in that: In step S2.3, the plasticizer is at least one of glycerol and sorbitol.

7. The method for preparing the palonosetron hydrochloride soft capsule according to claim 4, characterized in that: In step S2.3, the mass ratio of malic acid esterified modified gelatin, selenylated dextran, plasticizer and distilled water is (10-30): (1-10): (4-8): (50-90).

8. The method for preparing the palonosetron hydrochloride soft capsule according to claim 1, characterized in that: Step S3: Preparation of soft capsule contents, specifically comprising the following steps: S3.1: Add palonosetron hydrochloride to distilled water, stir until the palonosetron hydrochloride is completely dissolved, then add glycerol, stir and mix evenly to obtain a palonosetron hydrochloride solution, wherein the mixing mass ratio of palonosetron hydrochloride, distilled water and glycerol is (0.25-0.5):(3-5):(1-5); S3.2: Stir and mix caprylic acid capric acid mono- and diglycerides, polyglycerol oleate and butylated hydroxyanisole in a mass ratio of (100-120): (1-3): (0.1-0.5) to obtain an oil phase composition; S3.3: Under a nitrogen atmosphere, the palonosetron hydrochloride solution and the oil phase composition are stirred and mixed in a mass ratio of (1-2): (10-15) to obtain a mixed solution. Subsequently, the mixed solution is subjected to high-speed shearing by a high-speed shearing emulsifier under a nitrogen atmosphere at a shearing speed of 15000-22000 rpm and a shearing time of 3-5 min to obtain the contents of the soft capsule.

9. A palonosetron hydrochloride soft capsule, characterized in that: The palonosetron hydrochloride soft capsule is prepared by the preparation method of any one of claims 1 to 8.

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