Fonetuterol palonosetron oral taste-masking granule as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations as well as preparation and application thereof, and particularly relates to a fonetuterol palonosetron oral taste-masked granule as well as a preparation method and application of the fonetuterol palonosetron oral taste-masked granule. The fonetuterol palonosetron oral taste-masking granule disclosed by the invention is prepared from medicine carrying granules, an isolating layer, a taste-masking layer and a taste-modifying layer from inside to outside. The preparation method of the Fannetupitopapalonosetron oral taste-masking granules provided by the invention is simple to operate, and compared with a process of separately treating and preparing capsules, the Fannetupitopapalonosetron oral taste-masking granules are prepared in one step. The prepared product can be directly swallowed, and the compliance is improved. The fonetuterol palonosetron oral taste-masking granule prepared by the invention is used for preventing nausea and vomiting caused by chemotherapy, and has a good effect. The invention also provides a preparation method of the oral taste-masked Fannetupitant palonosetron granules.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, preparations and applications, and particularly relates to oral taste-masking granules of fornetupitant palonosetron and a preparation method and application thereof. Background Art

[0002] Helsinn Healthcare has developed related products including netupitant palonosetron capsules, fornetupitant palonosetron injection, and fornetupitant palonosetron injection.

[0003] Among them, Akynzeo ® The results of the original clinical study of ) showed that palonosetron and netupitant can prevent acute and delayed vomiting respectively, and are the first combination that acts on both NK-1 receptors and 5-HT3 receptors. Only one capsule is taken for one chemotherapy cycle, which improves the patient's medication compliance and has excellent antiemetic effect. It has high clinical application value in the field of chemotherapy antiemetic.

[0004] In order to provide a new route of administration for patients with oral intolerance, Helsinn Healthcare began to develop injection products. However, since netupitant is extremely slightly soluble in water, it cannot be prepared as an injection. Helsinn Healthcare developed fornetupitant by improving netupitant, which is a prodrug of netupitant. Its solubility reaches 11.5mg / ml at pH=10, making injection possible. After injection, fornetupitant can be rapidly converted into netupitant in the blood and take effect within 30 minutes. The original clinical data showed that the 260mg injection has similar pharmacokinetics to the 300mg capsule.

[0005] Although the injection has good clinical efficacy and benefits, there are still problems with clinical medication compliance. For example, when the fornetupitant palonosetron injection is used clinically, it needs to be diluted and prepared by the hospital nurse 30 minutes before the start of chemotherapy and dripped intravenously for more than 30 minutes. Compared with oral netupitant palonosetron capsules, the clinical use scenario is fixed and the use process is long. 50ml of injection is dripped for more than 30 minutes, which can easily cause patients to feel bored.

[0006] Netupitant Palonosetron Capsules are provided in the form of hard capsules and soft capsules. Although they are easy to take, the production process is complicated and the production cost is high. The EU review report discloses the production process of its tablets as follows: ① Mixing granulation materials and wet granulation, ② Drying whole granules, ③ Mixing the remaining excipients, ④ Tablet pressing, and ⑤ Bulk packaging. The production process of soft capsules is as follows: ① Prepare filling solution, ② Encapsulate into soft capsules and lubricate, ③ Drying and washing, ④ Bulk packaging. Then fill 3 tablets and 1 soft capsule into 0# hard capsules. Possible equipment: Tablet production (high shear wet granulator, fluidized bed or oven, hopper mixer, tablet press), soft capsule production (gel tank, vacuum mixing tank, colloid mill, soft capsule press, tray dryer, pill washing machine, light inspection table, filling: dual-channel capsule filling machine, etc.). Overall, tablet and soft capsule production need to be carried out in different workshops, equipment cannot be shared, there are many control points in the product production process, and the quality control risk is high. Summary of the invention

[0007] The technical problem to be solved by the present invention is to overcome the above-mentioned defects of the prior art, and provide a preparation method of oral taste-masking granules of fornetupitant palonosetron, which is simple to operate. Compared with the process of preparing capsules separately, the present invention is prepared in one step. The product prepared by the present invention can be swallowed directly, and the compliance is improved. The oral taste-masking granules of fornetupitant palonosetron prepared by the present invention are consistent with the clinical indications of the original research product, can be used to prevent nausea and vomiting caused by chemotherapy, and have a good effect.

[0008] The oral taste-masking granules of fornetupitant palonosetron of the present invention are made of drug-carrying particles, an isolation layer, a taste-masking layer and a flavor-correcting layer from the inside to the outside.

[0009] The unit preparation of drug-loaded particles, the unit preparation of isolation layer, the unit preparation of flavor-masking layer and the unit preparation of flavor-correcting layer are formulated in the following proportions by weight: 8302.05-16614.10 parts of drug-loaded particles, 90-220 parts of isolation layer, 651-1303 parts of flavor-masking layer and 40-100 parts of flavor-correcting layer.

[0010] The unit preparation of drug-loaded particles includes the following main components in parts by weight: 235-470 parts of fornetupitant, 0.25-0.50 parts of palonosetron, 20-50 parts of hydroxypropyl methylcellulose, 3.2-6.4 parts of disodium edetate, 43.6-87.2 parts of sodium hydroxide, and 8000-16000 parts of mannitol; the main drugs are fornetupitant and palonosetron, both of which are derived from the raw materials fornetupitant chloride hydrochloride and palonosetron hydrochloride. Mannitol with different average particle sizes is screened as a drug-loaded excipient for the unit preparation of drug-loaded particles. According to the particle preparation, particle taste and taste-masking effect evaluation, particles prepared with a particle size of 100-200 μm have good physical properties and taste effects, and a particle size of 200 μm is more preferred. The manufacturer and model of mannitol are ROQUETTE and the model is PEARLITOL. ® 200 SD.

[0011] The unit preparation of the isolation layer comprises the following main components in parts by weight: 80-200 parts of hypromellose and 10-20 parts of talc; The unit preparation of the taste masking layer comprises the following main components in parts by weight: 407-815 parts of Eudragit E PO, 40-81 parts of sodium lauryl sulfate, 61-122 parts of stearic acid, and 143-285 parts of magnesium stearate; The unit preparation of the flavoring layer includes the following main components in parts by weight: 5-15 parts of flavor, 5-15 parts of saccharin sodium, 20-50 parts of hypromellose, and 10-20 parts of talc.

[0012] The preparation method of the oral taste-masking granules of fornetupitant palonosetron comprises the following steps: (1) Preparing drug-loaded particles: dissolving sodium hydroxide in water, adding disodium edetate and fornetupitant chloride hydrochloride after dissolution, then adding palonosetron hydrochloride, adjusting the pH, and continuing to add hypromellose, stirring and dissolving to obtain a drug-containing solution, then spraying the drug-containing solution onto mannitol, drying and sieving to obtain drug-loaded particles; (2) coating the drug-loaded particles with an isolation layer: adding hydroxypropyl methylcellulose to water, dissolving and swelling it, adding talcum powder, dispersing it to obtain an isolation layer coating liquid, spraying the isolation layer coating liquid onto the drug-loaded particles, and drying them to obtain drug-loaded particles coated with an isolation layer; (3) coating the drug-loaded particles coated with the isolation layer with a taste-masking layer: adding sodium lauryl sulfate, stearic acid, Eudragit E PO, and magnesium stearate to water in sequence to dissolve them to obtain a taste-masking layer coating solution, spraying the taste-masking layer coating solution onto the drug-loaded particles coated with the isolation layer, and drying to obtain drug-loaded particles coated with the taste-masking layer; (4) Coating the drug-loaded particles coated with the taste-masking layer with a flavor-correcting layer: adding essence, sodium saccharin, and hydroxypropyl methylcellulose to water to dissolve and swell, then adding talcum powder and stirring to obtain a flavor-correcting layer coating liquid, spraying the flavor-correcting layer coating liquid onto the drug-loaded particles coated with the taste-masking layer, and drying to obtain fornetupitant palonosetron oral taste-masking granules.

[0013] In step (1), the pH is adjusted to 7.5-8.5, and a hydrochloric acid solution is used for adjusting the pH; and the sieve mesh number is 80 meshes.

[0014] During the spraying in step (2), step (3) and step (4), the material temperature is controlled to be 35-45°C.

[0015] In step (3), sodium lauryl sulfate, stearic acid, and Eudragit E PO are added to water in sequence, and then dispersed at a speed of 3000-4000 rpm until no solids float on the surface, and then magnesium stearate is added, and the stirring speed is adjusted to 6500-7500 rpm.

[0016] The taste-masking coating liquid in step (3) is passed through a 40-mesh sieve and stirred continuously during coating.

[0017] The drying temperature in step (2), step (3) and step (4) is 45° C. and the drying time is 5 min.

[0018] The application of the fornetupitant palonosetron oral taste-masking granules is to prevent nausea and vomiting caused by chemotherapy.

[0019] Specifically, the preparation method of the oral taste-masked granules of fornetupitant palonosetron comprises the following steps: 1. Preparation of drug-loaded particles 1.1 Weigh purified water, add the prescribed amount of sodium hydroxide, continue stirring to dissolve, then slowly add fornetupitant chloride hydrochloride, add disodium edetate and palonosetron hydrochloride after dissolution, stir and dissolve, use hydrochloric acid solution to adjust the pH to 7.5-8.5, then slowly add hypromellose, stir and dissolve, and continue stirring for 30 minutes to fully swell the hypromellose, and obtain a drug-containing solution. The fornetupitant chloride hydrochloride is calculated based on the prescribed amount of fornetupitant, and the palonosetron hydrochloride is calculated based on the prescribed amount of palonosetron.

[0020] 1.2 Weigh the prescribed amount of mannitol and place it in the fluidized bed. Turn on the air inlet for heating. When the temperature of mannitol reaches 40°C, turn on the spray to spray the drug-containing solution on the mannitol. The material temperature is controlled at 35-45°C during the process. After the spraying of the drug-containing solution is completed, adjust the air inlet temperature to 45°C and continue drying for 5 minutes.

[0021] 1.3 The dried granules were sieved with an 80-mesh sieve and the granules under the sieve were collected to obtain drug-loaded granules.

[0022] 2.Isolation layer coating of drug-loaded particles 2.1 Weigh the prescribed amount of HPMC and slowly add it into the purified water with continuous stirring. After it is fully dissolved and swollen, slowly add the prescribed amount of talc and stir and disperse it to obtain the isolation layer coating solution.

[0023] 2.2 Place the drug-loaded particles in a fluidized bed, turn on the air inlet for heating, and when the particle temperature reaches 40°C, turn on the spray to evenly spray the isolation layer coating liquid on the drug-loaded particles. The material temperature is controlled at 35-45°C during the process. After the spraying is completed, adjust the air inlet temperature to 45°C, continue drying for 5 minutes, and discharge the material to obtain drug-loaded particles coated with the isolation layer.

[0024] 3. Coat the drug-loaded particles with a taste-masking layer 3.1 Weigh purified water, then add the prescribed amount of sodium dodecyl sulfate and dissolve it under low-speed stirring in a high-shear homogenizer, then add the prescribed amount of stearic acid and Eudragit E PO, disperse at a speed of 3000-4000rpm until there is no solid floating on the surface, finally add the prescribed amount of magnesium stearate, adjust the dispersion stirring speed to 6500-7500rpm, and obtain the taste-masking layer coating solution. At this stage, evacuated foam may appear, which can be eliminated by reducing the speed. A total of 30 minutes are required to form a uniform dispersion. The taste-masking layer coating solution passes through a 40-mesh sieve. During coating, the taste-masking layer coating solution needs to be continuously stirred to prevent precipitation.

[0025] 3.2 Place the drug-loaded particles coated with the isolation layer in a fluidized bed, turn on the air supply for heating, and when the particle temperature reaches 40°C, turn on the spraying to evenly spray the taste-masking layer coating liquid on the particles. The material temperature is controlled at 35-45°C during the process. After the spraying is completed, adjust the air supply temperature to 45°C, continue drying for 5 minutes, and discharge the material to obtain the drug-loaded particles coated with the taste-masking layer.

[0026] 4. Coating the drug-loaded particles with the taste-masking layer with a flavor-correcting layer 4.1 Weigh purified water, add the prescribed amount of flavor, sodium saccharin, and hypromellose under stirring, continue stirring until dissolved and swollen, then add the prescribed amount of talcum powder and continue stirring for 15 minutes to obtain the flavor layer coating solution.

[0027] 4.2 Place the drug-loaded particles coated with the taste-masking layer in a fluidized bed, turn on the air inlet for heating, and when the particle temperature reaches 40°C, turn on the spray to evenly spray the flavor-correcting layer coating liquid on the particles. The material temperature is controlled at 35-45°C during the process. After the spraying is completed, adjust the air inlet temperature to 45°C, continue drying for 5 minutes, and discharge the material to obtain fornetupitant palonosetron oral taste-masking granules.

[0028] The isolation layer, taste-masking layer and flavor-correcting layer of the oral taste-masking granules of fornetupitant palonosetron of the present invention are coated on the drug-loaded particles in the form of coatings in sequence. The fornetupitant and palonosetron pharmaceutical composition is in the form of coatings that are coated on the drug particles of fornetupitant and palonosetron in sequence by making the isolation layer, taste-masking layer and flavor-correcting layer into coatings, so that the bitter taste of the drug is fully shielded. Compared with fornetupitant palonosetron injection, patient compliance is significantly improved under the premise of ensuring drug efficacy and bioavailability. Compared with netupitant palonosetron capsules, the production process is simplified and production efficiency is improved.

[0029] Compared with the prior art, the present invention has the following beneficial effects: (1) The oral taste-masked granules of fornetupitant and palonosetron prepared by the present invention change the administration route of fornetupitant and palonosetron from intravenous injection to oral administration, thereby improving patient compliance.

[0030] (2) The oral taste-masked granules of fornetupitant and palonosetron prepared by the present invention are administered orally. Compared with the traditional intravenous injection, the intravenous injection needs to control the speed and the drip time is longer than 30 minutes. Once the infusion is too fast, the blood drug concentration will increase rapidly, resulting in adverse reactions. However, after the fornetupitant and palonosetron are prepared into oral taste-masked granules, the dosage is changed to oral. Affected by the dissolution, absorption and distribution rates, the blood drug concentration is lower than that of the injection solution, and fornetupitant can be quickly converted into netupitant in the blood, which does not affect the efficacy and improves the safety of the patient's medication.

[0031] (3) Compared with the preparation methods of related oral dosage forms, the preparation method of the oral taste-masked granules of fornetupitant palonosetron of the present invention not only simplifies the production process, but also reduces the use of workshops and equipment, and the process is significantly optimized.

[0032] (4) The oral taste-masking granules of fornetupitant and palonosetron prepared by the present invention avoid the risk of fever. The oral taste-masking granules only need to control the microbial limit, that is, only a terminal sterilization process is required, while traditional injections need to be filtered and sterilized during the production process to ensure the sterility level. The sterilization control process involves a longer route and a higher risk. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 Schematic diagram of the dissolution curves of fornetupitant in Prescription 1, Prescription 2, and Prescription 3 in pH 2.0 hydrochloric acid solution.

[0034] Figure 2 Schematic diagram of the dissolution curves of palonosetron in Prescription 1, Prescription 2, and Prescription 3 in pH 2.0 hydrochloric acid solution.

[0035] Figure 3 This is a schematic diagram of the dissolution curves of fornetupitant in Prescription 1, Prescription 2, and Prescription 3 in pH 6.8 phosphate solution + 1% SDS.

[0036] Figure 4 Schematic diagram of the dissolution curves of palonosetron in Prescription 1, Prescription 2, and Prescription 3 in pH 6.8 phosphate solution + 1% SDS. DETAILED DESCRIPTION

[0037] The present invention will be further described below in conjunction with specific embodiments.

[0038] The raw materials used in the following examples and comparative examples are all commercially available products. The g in each of the following examples is measured as the same unit of weight parts, which is used as an explanation of the weight parts of the prescription described in the present invention. The process described below controls the material temperature at 35±5°C, which is the control of the operating temperature, and no further measurement of the specific temperature value is required. The mannitol with an average particle size of 200μm described below is produced by ROQUETTE, and the model is PEARLITOL ® 200 SD, 100 μm average particle size mannitol model is PEARLITOL ® 100 SD.

[0039] Example 1 The oral taste-masking granules of fornetupitant palonosetron are made of drug-loaded granules, an isolation layer, a taste-masking layer and a flavor-correcting layer from the inside to the outside. Prescription 1, Prescription 2, Prescription 3 and Prescription 4 are all prepared according to Table 1.

[0040] Table 1 Prescription information of fornetupitant palonosetron oral taste-masked granules

[0041] Example 2 The preparation method of the prescription 1 of the embodiment 1 comprises the following steps: 1. Preparation of drug-loaded particles 1.1 Weigh 20kg of purified water, add sodium hydroxide, continue to stir and dissolve, then slowly add fornetupitant chloride hydrochloride, add disodium edetate and palonosetron hydrochloride after dissolution, stir and dissolve, use hydrochloric acid solution to adjust pH to 8.0, then slowly add hypromellose, stir and dissolve, continue stirring for 30 minutes, and fully swell the hypromellose to obtain a drug-containing solution. The fornetupitant chloride hydrochloride is based on the prescription amount of fornetupitant, and the palonosetron hydrochloride is based on the prescription amount of palonosetron.

[0042] 1.2 Weigh mannitol and place it in the fluidized bed. Turn on the air inlet for heating. When the temperature of mannitol reaches 40°C, turn on the spray to spray the drug-containing solution on the mannitol. The material temperature is controlled at 35±5°C during the process. After the spraying of the drug-containing solution is completed, adjust the air inlet temperature to 45°C and continue drying for 5 minutes.

[0043] 1.3 The dried granules were sieved with an 80-mesh sieve and the granules under the sieve were collected to obtain drug-loaded granules.

[0044] 2.Isolation layer coating of drug-loaded particles 2.1 Weigh out Hydroxypropyl methylcellulose and slowly add it into 5 kg of purified water with continuous stirring. After it is fully dissolved and swollen, slowly add talcum powder and stir and disperse it to obtain the isolation layer coating solution.

[0045] 2.2 Place the drug-loaded particles in a fluidized bed, turn on the air inlet for heating, and when the particle temperature reaches 40°C, turn on the spray to evenly spray the isolation layer coating liquid on the drug-loaded particles. The material temperature is controlled at 35±5°C during the process. After the spraying is completed, adjust the air inlet temperature to 45°C, continue drying for 5 minutes, and discharge the material to obtain drug-loaded particles coated with the isolation layer.

[0046] 3. Coat the drug-loaded particles with a taste-masking layer 3.1 Weigh 3.4 kg of purified water, then add sodium lauryl sulfate and dissolve it under low-speed stirring in a high-shear homogenizer, then add stearic acid and Eudragit E PO, disperse at a speed of 3000 rpm until no solids float on the surface, finally add magnesium stearate, adjust the dispersion stirring speed to 6000 rpm, and obtain the taste-masking coating liquid. The evacuated foam that appears at this stage is eliminated by reducing the rotation speed, and a uniform dispersion is formed in 30 minutes. The taste-masking coating liquid passes through a 40-mesh sieve. During coating, the taste-masking coating liquid needs to be continuously stirred to prevent precipitation.

[0047] 3.2 Place the drug-loaded particles coated with the isolation layer in a fluidized bed, turn on the air supply for heating, and when the particle temperature reaches 40°C, turn on the spraying to evenly spray the taste-masking layer coating liquid on the particles. The material temperature is controlled at 35±5°C during the process. After the spraying is completed, adjust the air supply temperature to 45°C, continue drying for 5 minutes, and discharge the material to obtain the drug-loaded particles coated with the taste-masking layer.

[0048] 4. Coating the drug-loaded particles with the taste-masking layer with a flavor-correcting layer 4.1 Weigh 4 kg of purified water, add flavor, sodium saccharin and hypromellose under stirring, continue stirring until dissolved and swollen, then add talcum powder and continue stirring for 15 minutes to obtain the flavor layer coating solution.

[0049] 4.2 Place the drug-loaded particles coated with the taste-masking layer in a fluidized bed, turn on the air inlet for heating, and when the particle temperature reaches 40°C, turn on the spray to evenly spray the flavor-correcting layer coating liquid on the particles. The material temperature is controlled at 35±5°C during the process. After the spraying is completed, adjust the air inlet temperature to 45°C, continue drying for 5 minutes, and discharge the material to obtain fornetupitant palonosetron oral taste-masking granules.

[0050] Example 3 The preparation method of prescription 2 of embodiment 1 comprises the following steps: 1. Preparation of drug-loaded particles 1.1 Weigh 30kg of purified water, add sodium hydroxide, continue to stir and dissolve, then slowly add fornetupitant chloride hydrochloride, add disodium edetate and palonosetron hydrochloride after dissolution, stir and dissolve, use hydrochloric acid solution to adjust pH to 8.0, then slowly add hypromellose, stir and dissolve, continue stirring for 30min, make the hypromellose fully swell, and obtain a drug-containing solution. The fornetupitant chloride hydrochloride is based on the prescription amount of fornetupitant, and the palonosetron hydrochloride is based on the prescription amount of palonosetron.

[0051] 1.2 Weigh mannitol and place it in the fluidized bed, turn on the air inlet for heating. When the temperature of mannitol reaches 40°C, turn on the spray to spray the drug-containing solution on the mannitol. The material temperature is controlled at 35±5°C during the process (this place must be a range, and a single point cannot be operated). After the drug-containing solution is sprayed, adjust the air inlet temperature to 45°C and continue drying for 5 minutes.

[0052] 1.3 The dried granules were sieved with an 80-mesh sieve and the granules under the sieve were collected to obtain drug-loaded granules.

[0053] 2.Isolation layer coating of drug-loaded particles 2.1 Weigh out Hydroxypropyl methylcellulose and slowly add it into 7.5 kg of purified water with continuous stirring. After it is fully dissolved and swollen, slowly add talcum powder and stir and disperse it to obtain an isolation layer coating solution.

[0054] 2.2 Place the drug-loaded particles in a fluidized bed, turn on the air inlet for heating, and when the particle temperature reaches 40°C, turn on the spray to evenly spray the isolation layer coating liquid on the drug-loaded particles. The material temperature is controlled at 35±5°C during the process. After the spraying is completed, adjust the air inlet temperature to 45°C, continue drying for 5 minutes, and discharge the material to obtain drug-loaded particles coated with the isolation layer.

[0055] 3. Coat the drug-loaded particles with a taste-masking layer 3.1 Weigh 5.1 kg of purified water, then add sodium lauryl sulfate and dissolve it under low-speed stirring in a high-shear homogenizer, then add stearic acid and Eudragit E PO, disperse at a speed of 3500 rpm until no solids float on the surface, finally add magnesium stearate, adjust the dispersion stirring speed to 6500 rpm, and obtain the taste-masking coating liquid. The evacuated foam that appears at this stage is eliminated by reducing the rotation speed, and a uniform dispersion is formed in 30 minutes. The taste-masking coating liquid passes through a 40-mesh sieve. During coating, the taste-masking coating liquid needs to be continuously stirred to prevent precipitation.

[0056] 3.2 Place the drug-loaded particles coated with the isolation layer in a fluidized bed, turn on the air supply for heating, and when the particle temperature reaches 40°C, turn on the spraying to evenly spray the taste-masking layer coating liquid on the particles. The material temperature is controlled at 35±5°C during the process. After the spraying is completed, adjust the air supply temperature to 45°C, continue drying for 5 minutes, and discharge the material to obtain the drug-loaded particles coated with the taste-masking layer.

[0057] 4. Coating the drug-loaded particles with the taste-masking layer with a flavor-correcting layer 4.1 Weigh 6 kg of purified water, add flavor, sodium saccharin and hypromellose under stirring, continue stirring until dissolved and swollen, then add talcum powder and continue stirring for 15 minutes to obtain the flavor layer coating solution.

[0058] 4.2 Place the drug-loaded particles coated with the taste-masking layer in a fluidized bed, turn on the air inlet for heating, and when the particle temperature reaches 40°C, turn on the spray to evenly spray the flavor-correcting layer coating liquid on the particles. The material temperature is controlled at 35±5°C during the process. After the spraying is completed, adjust the air inlet temperature to 45°C, continue drying for 5 minutes, and discharge the material to obtain fornetupitant palonosetron oral taste-masking granules.

[0059] Example 4 The preparation method of Prescription 3 and Prescription 4 of Example 1 comprises the following steps: 1. Preparation of drug-loaded particles 1.1 Weigh 40kg of purified water, add sodium hydroxide, continue to stir and dissolve, then slowly add fornetupitant chloride hydrochloride, add disodium edetate and palonosetron hydrochloride after dissolution, stir and dissolve, use hydrochloric acid solution to adjust pH to 8.0, then slowly add hypromellose, stir and dissolve, continue stirring for 30 minutes, and fully swell the hypromellose to obtain a drug-containing solution. The fornetupitant chloride hydrochloride is based on the prescription amount of fornetupitant, and the palonosetron hydrochloride is based on the prescription amount of palonosetron.

[0060] 1.2 Weigh mannitol and place it in the fluidized bed. Turn on the air inlet for heating. When the temperature of mannitol reaches 40°C, turn on the spray to spray the drug-containing solution on the mannitol. The material temperature is controlled at 35±5°C during the process. After the spraying of the drug-containing solution is completed, adjust the air inlet temperature to 45°C and continue drying for 5 minutes.

[0061] 1.3 The dried granules were sieved with an 80-mesh sieve and the granules under the sieve were collected to obtain drug-loaded granules.

[0062] 2.Isolation layer coating of drug-loaded particles 2.1 Weigh out Hydroxypropyl methylcellulose and slowly add it into 10 kg of purified water with continuous stirring. After it is fully dissolved and swollen, slowly add talcum powder and stir and disperse it thoroughly to obtain the isolation layer coating solution.

[0063] 2.2 Place the drug-loaded particles in a fluidized bed, turn on the air inlet for heating, and when the particle temperature reaches 40°C, turn on the spray to evenly spray the isolation layer coating liquid on the drug-loaded particles. The material temperature is controlled at 35±5°C during the process. After the spraying is completed, adjust the air inlet temperature to 45°C, continue drying for 5 minutes, and discharge the material to obtain drug-loaded particles coated with the isolation layer.

[0064] 3. Coat the drug-loaded particles with a taste-masking layer 3.1 Weigh 6.8 kg of purified water, then add sodium lauryl sulfate and dissolve it under low-speed stirring in a high-shear homogenizer, then add stearic acid and Eudragit E PO, disperse at a speed of 4000 rpm until no solids float on the surface, finally add magnesium stearate, adjust the dispersion stirring speed to 7000 rpm, and obtain the taste-masking coating liquid. The evacuated foam that appears at this stage is eliminated by reducing the speed, and a uniform dispersion is formed in 30 minutes. The taste-masking coating liquid passes through a 40-mesh sieve. During coating, the taste-masking coating liquid needs to be continuously stirred to prevent precipitation.

[0065] 3.2 Place the drug-loaded particles coated with the isolation layer in a fluidized bed, turn on the air supply for heating, and when the particle temperature reaches 40°C, turn on the spraying to evenly spray the taste-masking layer coating liquid on the particles. The material temperature is controlled at 35±5°C during the process. After the spraying is completed, adjust the air supply temperature to 45°C, continue drying for 5 minutes, and discharge the material to obtain the drug-loaded particles coated with the taste-masking layer.

[0066] 4. Coating the drug-loaded particles with the taste-masking layer with a flavor-correcting layer 4.1 Weigh 8 kg of purified water, add flavor, sodium saccharin and hypromellose under stirring, continue stirring until dissolved and swollen, then add talcum powder and continue stirring for 15 minutes to obtain the flavor layer coating solution.

[0067] 4.2 Place the drug-loaded particles coated with the taste-masking layer in a fluidized bed, turn on the air inlet for heating, and when the particle temperature reaches 40°C, turn on the spray to evenly spray the flavor-correcting layer coating liquid on the particles. The material temperature is controlled at 35±5°C during the process. After the spraying is completed, adjust the air inlet temperature to 45°C, continue drying for 5 minutes, and discharge the material to obtain fornetupitant palonosetron oral taste-masking granules.

[0068] Comparative Example 1 Recipe 5 (drug-loaded particles only containing a flavoring layer) and Recipe 6 (drug-loaded particles only containing an isolation layer and a flavoring layer) were prepared according to Table 2. The production process was carried out according to the preparation steps in Example 2.

[0069] Table 2 Prescription information of the comparative example of fornetupitant palonosetron oral taste-masked granules

[0070] The oral taste-masked granules of fornetupitant and palonosetron prepared in the above examples and comparative examples were subjected to the following experimental evaluations. The powder properties of the drug-loaded granules prepared in prescriptions 1 and 4 were also compared.

[0071] (1) Taste experiment Ten volunteers were invited to conduct oral tasting evaluation on the drug-loaded granules, isolation layer granules, masking layer granules, flavor correction layer granules of prescription 1, prescription 5 granules, prescription 6 granules and prescription 4 granules. Among them, there were three boys and seven girls, aged between 23 and 40 years old.

[0072] Taste evaluation process: Volunteers slowly pour about 5g~6g of granules into the middle of the tongue (control the pouring position and do not overflow the edge of the tongue), stay for 30 seconds after pouring, let the saliva secretion soak the granules, then spit out the granules and fill in the taste experience. The evaluation is carried out from the following aspects: ① bitterness evaluation, ② acceptability, ③ taste evaluation. After tasting a granule, rinse the mouth with purified water for 30 seconds, and taste it again at least 5 minutes later. The results of the volunteers' taste evaluation and their analysis are shown in Tables 3 and 4.

[0073] Table 3 Summary of volunteers' oral evaluation results

[0074] Table 4 Analysis of the results of the volunteers' oral evaluation

[0075] It can be seen from Tables 3 and 4 above that prescription 1 of the present invention is only a drug-loaded particle. Because there is no coating to mask the taste, the bitterness rate reaches 100%, and all can feel astringency. The isolation layer particles of prescription 1 are swellable in water due to the hydroxypropyl methylcellulose, and 100% of the volunteers still feel a slight bitterness, and about 80% of the volunteers cannot accept the slight bitterness and slight astringency. 100% of the volunteers did not feel bitterness in the taste masking layer particles of prescription 1, indicating that the preliminary taste masking effect has been achieved, but the taste is not corrected. The acceptance of the taste correction layer particles of prescription 1 is 100%, and 100% of the volunteers feel that the taste is good. Although the particles of prescription 5 are coated with a taste correction layer, the bitterness rate still reaches 100%, and the particles have a poor taste. After the isolation layer of prescription 6 particles, the taste is improved but still general, and a slight bitter taste can still be felt after a period of time, and the acceptance of volunteers is only 30%. Although the particles of prescription 4 have no bitterness, due to the large amount of fine powder, the particles remaining on the tongue are more than the particles of prescription 1, and the taste is general. In summary, the best composition for the oral taste-masking granules of fornetupitant and palonosetron prepared by the present invention is the prescription of using mannitol (200 μm) to prepare the drug-loaded particles and then encapsulating the isolation layer, the taste-masking layer and the flavor-correcting layer.

[0076] (2) Comparison of drug-loaded particle powder properties Weigh 50g of prescription 1 and prescription 4 drug-loaded granules respectively, and use WQS type vibrating screen for sieving. The sieves are selected from the pharmacopoeia standard sieves of 80 mesh (180μm±7.6μm) and 120 mesh (125μm±5.8μm). Sieve for 1 minute with an amplitude of 1.0, and weigh the sieved materials and calculate the proportion. The calculation formula is: proportion % = sieved material weight (g) / 50g × 100%.

[0077] Table 5 Comparison of properties of mannitol granules prepared with different particle sizes

[0078] By comparing the properties of the above particles, it can be found that the particles prepared by 200μm mannitol have only 34% fine powder under the 120-mesh sieve. If taken in a short period of time, the particles will not absorb too much water to gelatinize. The particles prepared by 100μm mannitol have half particles and half fine powder. Although there is no bitter taste, the fine powder has a poor taste. In summary, the particles prepared by 200μm mannitol have the best properties, and the particles prepared by 100μm mannitol also have a good taste masking effect.

[0079] (3) Dissolution test The oral taste-masked granules of fornetupitant palonosetron prepared in Prescription 1, Prescription 2, and Prescription 3 were prepared according to the second method (paddle method) of Part 4 0931 Dissolution and Release Determination Method of the "Chinese Pharmacopoeia 2020 Edition", with pH 2.0 hydrochloric acid solution and pH 6.8 phosphate solution as the dissolution medium, with a volume of 1000 ml, a medium temperature of 37℃±0.5℃, a rotation speed of 50rpm, and sampling points of pH 2.0 medium (the medium was added with 1% sodium dodecyl sulfate, SDS): 5min, 10min, 15min, 30min, 45min, 60min; pH 6.8 medium: 30min, 60min, 90min, 120min.

[0080] The dissolution curve test results of fornetupitant in the pH 2.0 hydrochloric acid solution of Prescription 1, Prescription 2 and Prescription 3 are shown in Table 6. Figure 1 shown.

[0081] The dissolution curve test results of palonosetron in prescription 1, prescription 2 and prescription 3 in pH 2.0 hydrochloric acid solution are shown in Table 7. Figure 2 shown.

[0082] The dissolution curve test results of fornetupitant in prescription 1, prescription 2 and prescription 3 in pH 6.8 phosphate solution + 1% SDS are shown in Table 8. The dissolution curves are as follows: Figure 3 shown.

[0083] The dissolution curve test results of palonosetron in prescription 1, prescription 2 and prescription 3 in pH 6.8 phosphate solution + 1% SDS are shown in Table 9. Figure 4 shown.

[0084] Table 6 Dissolution curve test results of fornetupitant in pH 2.0 hydrochloric acid solution

[0085] Table 7 Dissolution curve test results of palonosetron in pH 2.0 hydrochloric acid solution

[0086] Table 8 Dissolution curve test results of fornetupitant in pH 6.8 phosphate solution + 1% SDS

[0087] Table 9 Dissolution curve test results of palonosetron in pH 6.8 phosphate solution + 1% SDS

[0088] Through Tables 6 to 9 above, and Figures 1 to 4It can be seen that the solubility of fornetupitant in pH 2.0 hydrochloric acid solution of Prescription 1, Prescription 2 and Prescription 3 can reach more than 85% in 45 minutes, and that of palonosetron can reach more than 95% in 10 minutes, indicating that the particles coated with Eudragit can be quickly dissolved under gastric acid conditions to release the drug-loaded particles, and will not limit the dissolution and release of the raw materials.

[0089] The solubility of fornetupitant and palonosetron in pH 6.8 phosphate solution of Prescription 1, Prescription 2, and Prescription 3 were all less than 5% at 30 min and less than 15% at 120 min, indicating that after coating with Eudragit EPO, saliva can be prevented from wetting the particles, thus preventing the raw materials from dissolving into saliva and producing a bitter taste.

Claims

1. An oral taste-masking granule of fornetupitant and palonosetron, characterized in that: From the inside to the outside, it is made of drug-carrying particles, an isolation layer, a taste-masking layer, and a flavor-correcting layer.

2. The oral taste-masking granules of fornetupitant and palonosetron according to claim 1, characterized in that: The unit preparation of the drug-loaded particles, the unit preparation of the isolation layer, the unit preparation of the taste-masking layer, and the unit preparation of the flavor-correcting layer are formulated in the following proportions by weight: 8302.05-16614.10 parts of the drug-loaded particles, 90-220 parts of the isolation layer, 651-1303 parts of the taste-masking layer, and 40-100 parts of the flavor-correcting layer. The drug-loaded particles are calculated based on fornetupitant and palonosetron.

3. The oral taste-masking granules of fornetupitant and palonosetron according to claim 2, characterized in that: The unit preparation of the drug-loaded particles includes the following main components in parts by weight: 235-470 parts of fornetupitant, 0.25-0.50 parts of palonosetron, 20-50 parts of hydroxypropyl methylcellulose, 3.2-6.4 parts of disodium edetate, 43.6-87.2 parts of sodium hydroxide, and 8000-16000 parts of mannitol.

4. The oral taste-masking granules of fornetupitant and palonosetron according to claim 2, characterized in that: The unit preparation of the isolation layer comprises the following main components in parts by weight: 80-200 parts of hydroxypropyl methylcellulose and 10-20 parts of talc.

5. The oral taste-masking granules of fornetupitant and palonosetron according to claim 2, characterized in that: The unit preparation of the taste masking layer comprises the following main components in parts by weight: 407-815 parts of Eudragit E PO, 40-81 parts of sodium lauryl sulfate, 61-122 parts of stearic acid, and 143-285 parts of magnesium stearate.

6. The oral taste-masking granules of fornetupitant and palonosetron according to claim 2, characterized in that: The unit preparation of the flavoring layer includes the following main components in parts by weight: 5-15 parts of flavor, 5-15 parts of saccharin sodium, 20-50 parts of hypromellose, and 10-20 parts of talc.

7. A method for preparing the oral taste-masked granules of fornetupitant and palonosetron according to any one of claims 1 to 6, characterized in that: The following steps are involved: (1) Preparing drug-loaded particles: dissolving sodium hydroxide in water, adding disodium edetate and fornetupitant chloride hydrochloride after dissolution, and then adding palonosetron hydrochloride, adjusting the pH to 7.5-8.5, and continuing to add hypromellose, stirring and dissolving to obtain a drug-containing solution, and then spraying the drug-containing solution onto mannitol, drying and sieving to obtain drug-loaded particles; (2) coating the drug-loaded particles with an isolation layer: adding hydroxypropyl methylcellulose to water, dissolving and swelling it, adding talcum powder, dispersing it to obtain an isolation layer coating liquid, spraying the isolation layer coating liquid onto the drug-loaded particles, and drying them to obtain drug-loaded particles coated with an isolation layer; (3) coating the drug-loaded particles coated with the isolation layer with a taste-masking layer: adding sodium lauryl sulfate, stearic acid, Eudragit E PO, and magnesium stearate to water in sequence to dissolve them to obtain a taste-masking layer coating solution, spraying the taste-masking layer coating solution onto the drug-loaded particles coated with the isolation layer, and drying to obtain drug-loaded particles coated with the taste-masking layer; (4) Coating the drug-loaded particles coated with the taste-masking layer with a flavor-correcting layer: adding essence, sodium saccharin, and hydroxypropyl methylcellulose to water to dissolve and swell, then adding talcum powder and stirring to obtain a flavor-correcting layer coating liquid, spraying the flavor-correcting layer coating liquid onto the drug-loaded particles coated with the taste-masking layer, and drying to obtain fornetupitant palonosetron oral taste-masking granules.

8. The method for preparing the oral taste-masking granules of fornetupitant and palonosetron according to claim 7, characterized in that: During the spraying in step (2), step (3) and step (4), the material temperature is controlled to be 35-45°C.

9. The method for preparing the oral taste-masking granules of fornetupitant and palonosetron according to claim 7, characterized in that: In step (3), sodium lauryl sulfate, stearic acid, and Eudragit E PO are added to water in sequence, and then dispersed at a speed of 3000-4000 rpm until no solids float on the surface, and then magnesium stearate is added, and the stirring speed is adjusted to 6500-7500 rpm.

10. An application of the oral taste-masking granules of fornetupitant and palonosetron according to any one of claims 1 to 6, characterized in that: Used to prevent nausea and vomiting caused by chemotherapy.

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