A sertraline hydrochloride direct-taking granule and a preparation method thereof

Abstract

The application provides a sertraline hydrochloride direct-taking granule and a preparation method thereof, and relates to the technical field of medicine preparation. The sertraline hydrochloride direct-taking granule prepared by the application is composed of drug-containing pellets and lubricants, and the drug-containing pellets comprise drug-containing pellet cores and taste masking layers from inside to outside. The direct-taking granule provided by the application can form a gel layer through sol-gel transition of the smooth structure of the surface layer after being wetted by oral saliva, so as to give the preparation the characteristics of swallowing lubrication, and effectively realize the water-free administration mode. The characteristics can significantly improve the drug compliance, and are especially suitable for the administration of special population of children.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, and in particular to a sertraline hydrochloride direct-acting granule and its preparation method. Background Technology

[0002] Sertraline hydrochloride, chemically known as (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylamine hydrochloride, is a white or off-white crystalline powder; odorless. Its structural formula is as follows: Sertraline hydrochloride is a selective serotonin reuptake inhibitor (SSRI) antidepressant developed and marketed by Pfizer in the early 1990s. It is used to treat symptoms of depression, including depression with or without a history of mania and accompanied by anxiety. Continued use of sertraline after satisfactory treatment can effectively prevent relapse and recurrence of depression. It is also used to treat obsessive-compulsive disorder (OCD). It is currently available in 96 countries and regions worldwide and still holds an irreplaceable position in the antidepressant market. Sertraline hydrochloride is the newest type of SRI. It works by inhibiting the reuptake of 5-HT at the presynaptic membrane, thereby increasing the concentration of 5-HT in the synaptic cleft and achieving its antidepressant effect. Compared to first-generation antidepressants such as monoamine oxidase inhibitors or tricyclic antidepressants, which simultaneously affect norepinephrine and dopamine levels, sertraline hydrochloride has fewer side effects due to its selectivity for the serotonin system, making it an attractive treatment option for adults and young children.

[0003] Sertraline hydrochloride is available in oral solutions, tablets, and capsules. For patients with difficulty swallowing solid dosage forms, existing orally disintegrating sertraline hydrochloride tablets are mostly produced using wet granulation, resulting in irregular particle shapes and uneven density. This leads to incomplete taste masking, large fluctuations in disintegration time, and unstable taste. Furthermore, relying solely on mixing the drug with alkaline oxides has limited taste masking effects, failing to meet the dual clinical requirements of taste and disintegration speed. Oral solutions use glycerol and ethanol as solvents, resulting in poor taste and poor medication adherence. Therefore, there is a demand for drug formulations that effectively improve medication adherence, especially those suitable for children. Summary of the Invention

[0004] Therefore, the purpose of this invention is to provide a sertraline hydrochloride direct-administered granule and its preparation method, so that the sertraline hydrochloride direct-administered granule is designed for anhydrous swallowing, making it a new option for children's medication.

[0005] The technical solution of this invention is implemented as follows: A sertraline hydrochloride direct-acting granule, the sertraline hydrochloride direct-acting granule comprising drug-containing microcapsules and a lubricant, the drug-containing microcapsules comprising a drug-containing core and a flavor-masking layer from the inside out; The drug-containing pellet core comprises the following ingredients: sertraline hydrochloride, diluent, binder, and disintegrant; The flavor-masking layer comprises the following raw materials: film-forming materials and anti-adhesion agents; The diluent is one or more of sucrose powder, mannitol, and starch; The adhesive is starch; The disintegrant is one or more of sodium carboxymethyl starch, crospovidone, low-substituted hydroxypropyl cellulose, and crospovidone carboxymethyl cellulose. The film-forming material is one or more of low-viscosity hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyvinylpyrrolidone.

[0006] This invention selects starch as the raw material for drug-containing pill cores. During the preparation of drug-containing pill cores, the property that starch is insoluble in water is used to form multiple pores in the starch slurry, so that the dried drug-containing pill cores form a porous structure and increase the surface area. At the same time, starch can quickly disintegrate when it comes into contact with water, which helps to further and rapidly release the active ingredients of the drug-containing pill cores and achieve an immediate release effect.

[0007] A further embodiment is that, by weight, the drug-containing pellet core comprises the following raw materials: 40-60 parts of sertraline hydrochloride, 5-20 parts of diluent, 1-5 parts of binder, 1-5 parts of disintegrant, and 0.1-0.3 parts of lubricant; The mass ratio of the film-forming material to the anti-adhesion agent is 1~3:0.2~1; The anti-adhesion agent is talc and / or micronized silica gel.

[0008] A further proposed method is to use a lubricant at a concentration of 0.3% to 0.6% of the weight of the medicated microcapsules. The mass ratio of the pill core to the flavor-masking layer is 18~22:1; The above weight ratios are dosage ratios calculated after removing the amount of purified water used in the pill core and flavor masking layer, and are all based on the weight of the above raw materials.

[0009] The lubricant is one or more of the following: magnesium stearate, calcium stearate, zinc stearate, aluminum stearate, stearic acid, talc, silica, micronized silica gel, polyethylene glycol, hydrogenated vegetable oil, sodium lauryl sulfate, fumaric acid, and polyoxyethylene monostearate.

[0010] A further embodiment is that the medicated pellet core and / or taste-masking layer also includes 0.25 to 2 parts of a taste-masking disintegration aid, wherein the taste-masking disintegration aid is magnesium aluminum silicate.

[0011] A further embodiment is that the amount of magnesium aluminum silicate in the drug-containing pellet core is 50% to 100% of the disintegrant mass; The amount of magnesium aluminum silicate used in the flavor-masking layer is 30% to 50% of the mass of the disintegrant.

[0012] Adding magnesium aluminum silicate, a taste-masking and disintegration aid, to the core of the medication pill allows it to hydrate and form a gel network that encapsulates the drug, further reducing the contact time between the drug and taste buds during direct administration. Adding magnesium aluminum silicate to the taste-masking layer, with its flake-like particles, helps improve the uniformity of the coating solution. Talc has relatively weak flowability, which is compensated for by the addition of magnesium aluminum silicate. Simultaneously, magnesium aluminum silicate expands in volume after absorbing water, causing HPMC to disintegrate more rapidly upon contact with water. Combined with its smooth texture, this significantly improves palatability for patients. Furthermore, it is important to control the amount of magnesium aluminum silicate used in the aforementioned core pill and / or taste-masking layer to avoid excessive dosage.

[0013] This invention provides a method for preparing sertraline hydrochloride granules, comprising the following steps: Preparation of S1 drug-containing pellet core: Sertraline hydrochloride, diluent, binder and disintegrant are mixed, dry-mixed, wet-granulated by adding binder aqueous solution, dried, and lubricant is added to obtain drug-containing pellet core; S2 Coating: Mix film-forming material and anti-adhesion agent, add water to make coating solution, spray the drug-containing pellet core with the solution, and dry to obtain coated pellets; S3 Finished Product: The coated pellets are mixed with a lubricant to obtain the sertraline hydrochloride direct-acting granules.

[0014] This invention uses an extrusion spherical pellet process to prepare spherical microspheres containing sertraline hydrochloride, diluent, binder and disintegrant, then coats the microspheres, and mixes them with a lubricant to form direct-acting granules; The method for preparing sertraline hydrochloride direct-acting granules may further include the following steps: S1 Drug-containing pill core preparation: Sertraline hydrochloride, diluent, binder, disintegrant and taste-masking disintegrant are mixed, dry-mixed, and wet-granulated by adding binder aqueous solution, and dried to obtain drug-containing pill core; S2 Coating: Mix film-forming material, anti-adhesion agent and / or taste-masking disintegration aid, add water to make coating solution, spray the drug-containing pellet core with the solution, and dry to obtain coated pellets; S3 Finished Product: The coated pellets are mixed with a lubricant to obtain the sertraline hydrochloride direct-acting granules.

[0015] Compared with traditional wet granulation, this invention forms a dense and uniform microsphere structure by extrusion and spheroidization, which allows the drug and flavor-masking components to fully combine and be encapsulated by the skeleton, significantly improving the flavor-masking effect and disintegration uniformity, while ensuring rapid drug dissolution.

[0016] This invention refines the parameters of wet granules obtained by the extrusion spheronization method and combines them with the control of coating parameters to prepare sertraline hydrochloride direct-acting granules with a dual structure, which makes the granules dissolve more stably and more bioequivalent (BE).

[0017] A further option is that, in step S1, a portion of the adhesive in the prescription is used to prepare an adhesive aqueous solution with a mass concentration of 3% to 10%, and the remaining adhesive in the prescription is dry-mixed with sertraline hydrochloride, diluent, and disintegrant. In step S1, during mixing, the stirring paddle speed is set to 3. 6 r / s, cutting blade speed 25 35 r / s; The dry mixing time is 3 to 10 minutes; the adhesive aqueous solution is added within the first 2 to 4 minutes of dry mixing.

[0018] A further option is that, in step S1, wet granules are obtained by extrusion spheronization, with the extrusion speed set to 10~50 rpm; after extrusion, a shot blasting step is also included, with the shot blasting speed set to 500~1000 rpm and the time set to 20~80 s.

[0019] A further option is to set the coating parameters in step S2 as follows: outlet air temperature is 20~60℃, inlet air temperature is 20~80℃, atomization pressure is 0.1~0.4 MPa, and material temperature is 30~50℃.

[0020] A further embodiment is characterized in that, in step S3, the mixing speed is set to 5~15 r / min and the mixing time is set to 2~10 min. Compared with the prior art, the beneficial effects of the present invention are as follows: (1) The sertraline hydrochloride direct-administered granules prepared by the present invention are composed of drug-containing microspheres and lubricant, and have a simple and stable structure. After being moistened by saliva in the mouth, the smooth surface structure of the direct-administered granules provided by the present invention can undergo a sol-gel transformation and form a gel layer, giving the formulation swallowing lubrication properties and realizing a waterless administration method; this property can significantly improve medication compliance, and is especially suitable for administration to special populations such as children.

[0021] (2) Stronger and more stable taste masking: Compared with the original oral solid dosage form, the drug in the direct-taken granules prepared by the present invention is wrapped in the skeleton. The bitter taste is not released when the oral cavity is in short contact, which can effectively mask the unpleasant smell of the raw drug and optimize the taste of the drug.

[0022] (3) Faster and more uniform disintegration: The present invention uses diluent, binder and disintegrant to form drug-containing pellet core with the main drug, and combines film-forming material and anti-adhesion agent as coating liquid to form taste masking layer. The dual structure makes the micro pellets have a large specific surface area and controllable pore structure, which can effectively achieve rapid disintegration and minimal batch-to-batch differences. (4) More stable dissolution: The drug-containing microcapsules disintegrate rapidly and reach equilibrium, avoiding the inconsistent dissolution of particles produced by wet granulation, and making it easier to achieve consistent BE.

[0023] (5) This invention innovates traditional drug delivery dosage forms, optimizes the portability and ease of administration of the formulation, fills the market technology gap of no direct-administered dosage form for this product, and improves the drug dosage form system. Attached Figure Description

[0024] Figure 1 This is a dissolution curve of the sertraline hydrochloride direct-acting granules prepared in Example 1 of the present invention; Figure 2 This is a dissolution curve of the sertraline hydrochloride direct-acting granules prepared in Example 2 of the present invention; Figure 3 This is a dissolution curve of the sertraline hydrochloride direct-acting granules prepared in Example 3 of the present invention; Figure 4 The dissolution curve of the sertraline hydrochloride direct-acting granules prepared in Comparative Example 1 of this invention is shown. Figure 5 This is a dissolution curve of the sertraline hydrochloride direct-acting granules prepared in Example 4 of the present invention; Figure 6 The image shows a radar diagram of the sertraline hydrochloride direct-acting granules prepared according to the present invention, where 1 is Example 6, 2 is Example 5, 3 is Example 4, and 4 is Example 1; CO0: bitterness, BTO: bitterness of hydrochloride, ANO: aftertaste of bitterness, AE1: astringency, GL1: sweetness, CPA(CO0): aftertaste of sour and bitterness, and CPA(AE1): aftertaste of astringency. Detailed Implementation

[0025] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0026] Unless otherwise specified, the experimental methods used in the embodiments of this invention are all conventional methods.

[0027] Unless otherwise specified, all materials and reagents used in the embodiments of this invention are commercially available.

[0028] The method for determining dissolution is as follows: the method for determining dissolution and release in the 2025 edition of the Chinese Pharmacopoeia (General Rule 0931, Method II).

[0029] Dissolution conditions: 900 mL of pH 4.5 sodium acetate buffer solution was used as the dissolution medium, and the rotation speed was 50 rpm.

[0030] Example 1 The composition of sertraline hydrochloride direct-acting granules is as follows: Table 1. Composition of Sertraline Hydrochloride Direct-Administer Granules

[0031] The preparation method is as follows: (1) Preparation of drug-containing pill core: Add solvent 1 purified water to the pulping pot, and disperse the 25% starch of the prescription amount evenly under stirring. Turn on the steam to heat and cook until the starch slurry is generated, and prepare 6% starch slurry for later use.

[0032] Add sertraline hydrochloride, starch, sucrose powder, and croscarmellose sodium to a wet granulator according to the dosages in Table 1, and set the agitator speed to 3. 6 r / s, cutting blade speed 25 Mix at 35 rpm for 3 minutes, then add 6% starch slurry to granulate within 3 minutes, and continue mixing for 2 minutes.

[0033] Depending on the particle formation, solvent 2 can be added in stages. The agitator speed should be set to 3. The cutting blade speed is set to 25 rpm at 6 r / s. 35 r / s. After each addition of solvent 2, the granulation time is 0.5~1 min to obtain soft material.

[0034] The soft material is placed in an extruder and extruded at a speed of 10-50 rpm with a perforated plate diameter of 0.4 mm. Then it is transferred to a shot blasting machine for shot blasting at a speed of 500-1000 rpm for 20-80 s to obtain wet granules.

[0035] Spread the wet granules on a tray in an oven and place it in an oven at 55℃±5℃. Dry until the moisture content is ≤2%. The dried medicated pellet cores are then sieved through a 30-mesh sieve to remove large particles and a 45-mesh sieve to remove fine powder, thus obtaining the medicated pellet cores.

[0036] (2) Flavoring film coating: Heat 1 / 3 of the amount of purified water in the flavoring layer prescription to 80-100℃, add hydroxypropyl methylcellulose E5 and sucrose powder in sequence while stirring, and after they are completely dissolved, add the remaining purified water and the amount of talc in the prescription to make a suspension. Coat the drug-containing pill core with a flavoring film by bottom spray coating in a granulation coating machine. After the spraying is completed, dry the product for 10 minutes to make coated pills.

[0037] The coating process parameters are: outlet air temperature: 20°C 60℃, inlet air temperature: 20℃ 80℃, atomization pressure: 0.1 0.4 MPa, material temperature: 30-50℃.

[0038] (3) Lubrication: Mix sertraline hydrochloride microspheres with magnesium stearate at a mixing speed of 10 r / min for 5 min.

[0039] The dissolution curve of the sertraline hydrochloride direct-acting granules prepared in this embodiment is shown in the figure below. Figure 1 As shown.

[0040] Example 2 The composition of sertraline hydrochloride direct-acting granules is as follows: Table 2 Composition of Sertraline Hydrochloride Direct-Administer Granules

[0041] The preparation method is as follows: (1) Preparation of drug-containing pill core: Add solvent 1 purified water to the pulping pot, and disperse the 25% starch of the prescription amount evenly under stirring. Turn on the steam to heat and cook until the starch slurry is generated, and prepare 6% starch slurry for later use.

[0042] Add sertraline hydrochloride, mannitol, sucrose powder, starch, and croscarmellose sodium to the wet granulator according to the prescription in Table 2, and set the agitator speed to 3. 6 r / s, cutting blade speed 25 Mix at 35 rpm for 3 minutes, then add 6% starch slurry to granulate within 3 minutes, and continue mixing for 2 minutes.

[0043] Depending on the particle formation, solvent 2 can be added in stages. The agitator speed should be set to 3. The cutting blade speed is set to 25 rpm at 6 r / s. 35 r / s. After each addition of solvent 2, the granulation time is 0.5~1 min to obtain soft material.

[0044] The soft material is placed in an extruder and extruded at a speed of 10-50 rpm with a perforated plate diameter of 0.4 mm. Then it is transferred to a shot blasting machine for shot blasting at a speed of 500-1000 rpm for 20-80 s to obtain wet granules.

[0045] Spread the wet granules on a tray in an oven and place it in an oven at 55℃±5℃. Dry until the moisture content is ≤2%. The dried medicated pellet cores are then sieved through a 30-mesh sieve to remove large particles and a 45-mesh sieve to remove fine powder, thus obtaining the medicated pellet cores.

[0046] (2) Flavoring film coating: Heat 1 / 3 of the amount of purified water in the flavoring layer prescription to 80-100℃, add hydroxypropyl methylcellulose E5 and mannitol in sequence while stirring, and after they are completely dissolved, add the remaining purified water and the amount of talc in the prescription to make a suspension. Coat the drug-containing pill core with a flavoring film by bottom spray coating in a granulation coating machine. After the spraying is completed, dry the product for 10 minutes to make coated pills.

[0047] The coating process parameters are: outlet air temperature: 20°C 60℃, inlet air temperature: 20℃ 80℃, atomization pressure: 0.1 0.4 MPa, material temperature: 30-50℃.

[0048] (3) Lubrication: Mix sertraline hydrochloride microspheres with magnesium stearate at a mixing speed of 10 r / min for 5 min.

[0049] The dissolution curve of the sertraline hydrochloride direct-acting granules prepared in this embodiment is shown in the figure below. Figure 2 As shown.

[0050] Example 3 The composition of sertraline hydrochloride direct-acting granules is as follows: Table 3 Composition of Sertraline Hydrochloride Direct Granules

[0051] The preparation method is as follows: (1) Preparation of drug-containing pill core: Add solvent 1 purified water to the pulping pot, and disperse the 25% starch of the prescription amount evenly under stirring. Turn on the steam to heat and cook until the starch slurry is generated, and prepare 6% starch slurry for later use.

[0052] Add sertraline hydrochloride, starch, sucrose powder, sorbitol, and croscarmellose sodium to the wet granulator according to the prescription in Table 3, and set the agitator speed to 3. 6 r / s, cutting blade speed 25 Mix at 35 rpm for 3 minutes, then add 6% starch slurry to granulate within 3 minutes, and continue mixing for 2 minutes.

[0053] Depending on the particle formation, solvent 2 can be added in stages. The agitator speed should be set to 3. The cutting blade speed is set to 25 rpm at 6 r / s. 35 r / s. After each addition of solvent 2, the granulation time is 0.5~1 min to obtain soft material.

[0054] The soft material is placed in an extruder and extruded at a speed of 10-50 rpm with a perforated plate diameter of 0.4 mm. Then it is transferred to a shot blasting machine for shot blasting at a speed of 500-1000 rpm for 20-80 s to obtain wet granules.

[0055] Spread the wet granules on a tray in an oven and place it in an oven at 55℃±5℃. Dry until the moisture content is ≤2%. The dried medicated pellet cores are then sieved through a 30-mesh sieve to remove large particles and a 45-mesh sieve to remove fine powder, thus obtaining the medicated pellet cores.

[0056] (2) Flavoring film coating: Heat 1 / 3 of the amount of purified water in the flavoring layer prescription to 80-100℃, add hydroxypropyl methylcellulose E5 and sucralose in sequence while stirring, and after they are completely dissolved, add the remaining purified water and the amount of talc in the prescription to make a suspension. Coat the drug-containing pill core with a flavoring film by bottom spray coating in a granulation coating machine. After the spraying is completed, dry the product for 10 minutes to make coated pills.

[0057] The coating process parameters are: outlet air temperature: 20°C 60℃, inlet air temperature: 20℃ 80℃, atomization pressure: 0.1 0.4 MPa, material temperature: 30-50℃.

[0058] (3) Lubrication: Mix sertraline hydrochloride microspheres with magnesium stearate at a mixing speed of 10 r / min for 5 min.

[0059] The dissolution curve of the sertraline hydrochloride direct-acting granules prepared in this embodiment is shown in the figure below. Figure 3 As shown.

[0060] Comparative Example 1 The difference between this comparative example and Example 3 is that purified water was used for granulation. The specific composition of the sertraline hydrochloride direct-acting granules is as follows: Table 4 Composition of Sertraline Hydrochloride Direct-Administer Granules

[0061] The preparation method is as follows: (1) Preparation of drug-containing pellet cores: According to the prescription in Table 4, add sertraline hydrochloride, starch, sucrose powder, sorbitol and croscarmellose sodium to a wet granulator. Set the stirring paddle speed to 3-6 r / s and the cutting blade speed to 25-35 r / s. Dry mix for 3 min. Add purified water (solvent 2) within 3 min to granulate. Continue mixing for 2 min to obtain soft material. Place the soft material in an extruder and extrude it at a speed of 10-50 rpm with a perforated plate diameter of 0.4 mm. Then transfer it to a shot blasting machine for shot blasting at a speed of 500-1000 rpm for 20-80 s to obtain wet granules.

[0062] Spread the wet granules on a tray in an oven and place it in an oven at 55℃±5℃. Dry until the moisture content is ≤2%. The dried medicated pellet cores are then sieved through a 30-mesh sieve to remove large particles and a 45-mesh sieve to remove fine powder, thus obtaining the medicated pellet cores.

[0063] (2) Flavoring film coating: Heat 1 / 3 of the amount of purified water in the flavoring layer prescription to 80-100℃, add hydroxypropyl methylcellulose E5 and sucrose powder in sequence while stirring, and after they are completely dissolved, add the remaining purified water and the amount of talc in the prescription to make a suspension. Coat the drug-containing pill core with a flavoring film by bottom spray coating in a granulation coating machine. After the spraying is completed, dry the product for 10 minutes to make coated pills.

[0064] The coating process parameters are: outlet air temperature: 20°C 60℃, inlet air temperature: 20℃ 80℃, atomization pressure: 0.1 0.4 MPa, material temperature: 30-50℃.

[0065] (3) Lubrication: Mix sertraline hydrochloride microspheres with magnesium stearate at a mixing speed of 10 r / min for 5 min.

[0066] The dissolution curve of the sertraline hydrochloride granules prepared in this comparative example is shown in the figure below. Figure 4 As shown, the cumulative release rate after 60 hours is only 80%, indicating that when using purified water for granulation, the dissolution rate is low, making it impossible to achieve the goal of rapid drug release into the stomach and thus difficult to achieve a rapid onset of action.

[0067] Comparative Example 2 The difference between this comparative example and Example 1 is that the film-forming material is different. Specifically, the composition of the sertraline hydrochloride direct-acting particles is as follows: Table 5 Composition of Sertraline Hydrochloride Direct-Administer Granules

[0068] Except for the addition of carbomer in step (2) of coating solution preparation, the other steps are the same as those in Example 1.

[0069] Test Example 1 Evaluation indicators: 1. Swallow without water: Sertraline hydrochloride granules prepared in Example 1 and Comparative Example 2 were tested by 23 volunteers (10 males and 13 females, with an average age of 13 years) for anhydrous swallowing. The volunteers reported that the amount and speed of saliva secretion after the granules of Example 1 and Comparative Example 2 entered the oral cavity were sufficient to meet the requirements for drug swallowing, and the medication could be taken within 2 minutes.

[0070] 2. Palatability evaluation: The palatability of the pharmaceutical preparations of Example 1 and Comparative Example 2 was evaluated using the visual analog scoring (VAS) method. The perception time of bitterness and sweetness, solubility, and gritty texture were scored. The evaluation criteria are shown in Table 6 below.

[0071] Table 6 Scoring Criteria and Scores

[0072] Volunteers understood the above evaluation criteria and conducted independent tasting and evaluation. In Example 1, over 90% of the participants had a VAS score of 50 or higher, while in Example 2, the proportion of participants with a VAS score of 50 or higher was 80%.

[0073] Example 4 The difference between this embodiment and Embodiment 1 is that a taste-masking and disintegration aid is added to the core of the granules. The specific composition of the sertraline hydrochloride direct-acting granules is as follows: Table 7 Composition of Sertraline Hydrochloride Direct-Administer Granules

[0074] The preparation method is as follows: (1) Preparation of drug-containing pill core: Add solvent 1 purified water to the pulping pot, and disperse the 25% starch of the prescription amount evenly under stirring. Turn on the steam to heat and cook until the starch slurry is generated, and prepare 6% starch slurry for later use.

[0075] Add sertraline hydrochloride, starch, sucrose powder, croscarmellose sodium, and magnesium aluminum silicate to the wet granulator according to the prescription in Table 7, and set the stirring paddle speed to 3. 6 r / s, cutting blade speed 25 Mix at 35 rpm for 3 minutes, then add 6% starch slurry to granulate within 3 minutes, and continue mixing for 2 minutes.

[0076] Depending on the particle formation, solvent 2 can be added in stages. The agitator speed should be set to 3. The cutting blade speed is set to 25 rpm at 6 r / s. 35 r / s. After each addition of solvent 2, the granulation time is 0.5~1 min to obtain soft material.

[0077] The subsequent steps are the same as in Example 1.

[0078] The dissolution curve of the sertraline hydrochloride direct-acting granules prepared in this embodiment is shown in the figure below. Figure 5 As shown.

[0079] Example 5 The difference between this embodiment and Embodiment 1 is that a taste-masking disintegration aid is added to the pill core and taste-masking layer. The specific composition of the sertraline hydrochloride direct-acting granules is as follows: Table 8 Composition of Sertraline Hydrochloride Direct-Administer Granules

[0080] The preparation method is as follows: (1) Preparation of drug-containing pill core: Add solvent 1 purified water to the pulping pot, and disperse the 25% starch of the prescription amount evenly under stirring. Turn on the steam to heat and cook until the starch slurry is generated, and prepare 6% starch slurry for later use.

[0081] Add sertraline hydrochloride, starch, sucrose powder, croscarmellose sodium, and magnesium aluminum silicate to the wet granulator according to the prescription in Table 8, and set the stirring paddle speed to 3. 6 r / s, cutting blade speed 25 Mix at 35 rpm for 3 minutes, then add 6% starch slurry to granulate within 3 minutes, and continue mixing for 2 minutes.

[0082] Depending on the particle formation, solvent 2 can be added in stages. The agitator speed should be set to 3. The cutting blade speed is set to 25 rpm at 6 r / s. 35 r / s. After each addition of solvent 2, the granulation time is 0.5~1 min to obtain soft material.

[0083] The soft material is placed in an extruder and extruded at a speed of 10-50 rpm with a perforated plate diameter of 0.4 mm. Then it is transferred to a shot blasting machine for shot blasting at a speed of 500-1000 rpm for 20-80 s to obtain wet granules.

[0084] Spread the wet granules on a tray in an oven and place it in an oven at 55℃±5℃. Dry until the moisture content is ≤2%. The dried medicated pellet cores are then sieved through a 30-mesh sieve to remove large particles and a 45-mesh sieve to remove fine powder, thus obtaining the medicated pellet cores.

[0085] (2) Flavoring film coating: Heat 1 / 3 of the amount of purified water in the flavoring layer prescription to 80-100℃, and add hydroxypropyl methylcellulose E5, sucrose powder and magnesium aluminum silicate in sequence while stirring. After complete dissolution, add the remaining purified water and the amount of talc in the prescription to make a suspension. Coat the drug-containing pill core with a flavoring film by bottom spray coating in a granulation coating machine. After spraying, dry the product for 10 minutes to make coated pills.

[0086] The coating process parameters are: outlet air temperature: 20°C 60℃, inlet air temperature: 20℃ 80℃, atomization pressure: 0.1 0.4 MPa, material temperature: 30-50℃.

[0087] (3) Lubrication: Mix sertraline hydrochloride microspheres with magnesium stearate at a mixing speed of 10 r / min for 5 min.

[0088] Example 6 The difference between this embodiment and Embodiment 1 is that a taste-masking disintegration aid is added to the pill core and taste-masking layer. The specific composition of the sertraline hydrochloride direct-acting granules is as follows: Table 9 Composition of Sertraline Hydrochloride Direct-Administer Granules

[0089] The preparation method is as follows: (1) Preparation of drug-containing pill core: Add solvent 1 purified water to the pulping pot, and disperse the 25% starch of the prescription amount evenly under stirring. Turn on the steam to heat and cook until the starch slurry is generated, and prepare 6% starch slurry for later use.

[0090] Add sertraline hydrochloride, starch, sucrose powder, croscarmellose sodium, and magnesium aluminum silicate to the wet granulator according to the prescription in Table 9, and set the stirring paddle speed to 3. 6 r / s, cutting blade speed 25 Mix at 35 rpm for 3 minutes, then add 6% starch slurry to granulate within 3 minutes, and continue mixing for 2 minutes.

[0091] Depending on the particle formation, solvent 2 can be added in stages. The agitator speed should be set to 3. The cutting blade speed is set to 25 rpm at 6 r / s. 35 r / s. After each addition of solvent 2, the granulation time is 0.5~1 min to obtain soft material.

[0092] The soft material is placed in an extruder and extruded at a speed of 10-50 rpm with a perforated plate diameter of 0.4 mm. Then it is transferred to a shot blasting machine for shot blasting at a speed of 500-1000 rpm for 20-80 s to obtain wet granules.

[0093] Spread the wet granules on a tray in an oven and place it in an oven at 55℃±5℃. Dry until the moisture content is ≤2%. The dried medicated pellet cores are then sieved through a 30-mesh sieve to remove large particles and a 45-mesh sieve to remove fine powder, thus obtaining the medicated pellet cores.

[0094] (2) Flavoring film coating: Heat 1 / 3 of the amount of purified water in the flavoring layer prescription to 80-100℃, and add hydroxypropyl methylcellulose E5, sucrose powder and magnesium aluminum silicate in sequence while stirring. After complete dissolution, add the remaining purified water and the amount of talc in the prescription to make a suspension. Coat the drug-containing pill core with a flavoring film by bottom spray coating in a granulation coating machine. After spraying, dry the product for 10 minutes to make coated pills.

[0095] The coating process parameters are: outlet air temperature: 20°C 60℃, inlet air temperature: 20℃ 80℃, atomization pressure: 0.1 0.4 MPa, material temperature: 30-50℃.

[0096] (3) Lubrication: Mix sertraline hydrochloride microspheres with magnesium stearate at a mixing speed of 10 r / min for 5 min.

[0097] Test Example 2 Evaluation indicators: 1. Odor masking effect The masking effect was evaluated using the INSENT TS-5000Z taste analysis system from Japan. The testing methods were based on those of WOERTZ K, TISSEN C, and KLEINEBUDDE P. et al The performance qualification of an electronic tongue based on ICH guideline Q2 was modified accordingly; the reference solution consisted of potassium chloride at a final concentration of 30 mM and tartaric acid at a final concentration of 0.3 mM. The reference solution was a 10 mM potassium chloride solution. The direct-acting granules prepared in Examples 1 and 4-6 were dissolved in the reference solution at a sample concentration of 1.344 g / L. Each sample was measured four times, and each measurement included determining the response value of the reference solution. The taste response value of each sensor was calculated based on the response value of the reference solution. The results are as follows. Figure 6 .

[0098] Depend on Figure 6 It can be seen that the samples all responded to the AN0, AE1 and GL1 sensors. The difference in response of each sample to different sensors was not significant. The sample with the strongest response to the AN0 bitterness sensor was Example 1. The addition of magnesium aluminum silicate reduced the bitterness value.

[0099] 2. Disintegration effect Referring to the disintegration time test method in Part IV of the 2025 edition of the Chinese Pharmacopoeia, the disintegration time of sertraline hydrochloride direct-administered granules was determined at a temperature of 37℃ ± 1℃ using water as the medium. The results are as follows: Table 10 Disintegration time and appearance of sertraline hydrochloride granules

[0100] Note: Medium indicates that the film is relatively smooth and has a relatively uniform color; Good indicates that the film is smooth and has a uniform color.

[0101] As shown in Table 10, the disintegration time of the sertraline hydrochloride direct-acting granules prepared by the present invention is <60s. Among them, the disintegration time of Examples 4-6 is basically <30s. The addition of magnesium aluminum silicate has better disintegration properties and faster in vitro dissolution.

[0102] The above description represents the preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications are also considered to be within the scope of protection of the present invention.

Claims

1. A sertraline hydrochloride direct-acting granule, characterized in that, The sertraline hydrochloride direct-acting granules include drug-containing microcapsules and a lubricant, wherein the drug-containing microcapsules include a drug-containing core and a flavor-masking layer from the inside out; The drug-containing pellet core comprises the following ingredients: sertraline hydrochloride, diluent, binder, and disintegrant; The flavor-masking layer comprises the following raw materials: film-forming materials and anti-adhesion agents; The diluent is one or more of sucrose powder, mannitol, and starch; The adhesive is starch; The disintegrant is one or more of sodium carboxymethyl starch, crospovidone, low-substituted hydroxypropyl cellulose, and crospovidone carboxymethyl cellulose. The film-forming material is one or more of low-viscosity hydroxypropyl methylcellulose, hydroxypropyl cellulose, and povidone.

2. The sertraline hydrochloride direct-acting granules according to claim 1, characterized in that, By weight, the drug-containing pellet core comprises the following raw materials: 40-60 parts of sertraline hydrochloride, 5-20 parts of diluent, 1-5 parts of binder, 1-5 parts of disintegrant, and 0.1-0.3 parts of lubricant; The mass ratio of the film-forming material to the anti-adhesion agent is 1~3:0.2~1; The anti-adhesion agent is talc and / or micronized silica gel.

3. The sertraline hydrochloride direct-acting granules according to claim 1, characterized in that, The amount of lubricant used is 0.3% to 0.6% of the weight of the medicated microcapsules; The mass ratio of the pill core to the flavor-masking layer is 18~22:1 The lubricant is one or more of the following: magnesium stearate, calcium stearate, zinc stearate, aluminum stearate, stearic acid, talc, silica, micronized silica gel, polyethylene glycol, hydrogenated vegetable oil, sodium lauryl sulfate, fumaric acid, and polyoxyethylene monostearate.

4. The sertraline hydrochloride direct-acting granules according to claim 1 or 2, characterized in that, The medicated pellet core and / or taste-masking layer also include 0.25 to 2 parts of a taste-masking disintegration aid, wherein the taste-masking disintegration aid is magnesium aluminum silicate.

5. The sertraline hydrochloride direct-acting granules according to claim 4, characterized in that, The amount of magnesium aluminum silicate in the drug-containing pellet core is 50% to 100% of the disintegrant mass; The amount of magnesium aluminum silicate used in the flavor-masking layer is 30% to 50% of the mass of the disintegrant.

6. A method for preparing sertraline hydrochloride direct-acting granules as described in any one of claims 1 to 5, characterized in that, Includes the following steps: S1 Drug-containing pellet core preparation: Sertraline hydrochloride, diluent, binder and disintegrant are mixed, dry-mixed, and wet-granulated by adding an aqueous binder solution, and dried to obtain drug-containing pellet core; S2 Coating: Mix film-forming material and anti-adhesion agent, add water to make coating solution, spray the drug-containing pellet core with the solution, and dry to obtain coated pellets; S3 Finished product: The coated pellets are mixed with a lubricant to obtain the sertraline hydrochloride direct-acting granules; The method for preparing sertraline hydrochloride direct-acting granules may further include the following steps: S1 Drug-containing pill core preparation: Sertraline hydrochloride, diluent, binder, disintegrant and taste-masking disintegrant are mixed, dry-mixed, and wet-granulated by adding binder aqueous solution, and dried to obtain drug-containing pill core; S2 Coating: Mix film-forming material, anti-adhesion agent and / or taste-masking disintegration aid, add water to make coating solution, spray the drug-containing pellet core with the solution, and dry to obtain coated pellets; S3 Finished Product: The coated pellets are mixed with a lubricant to obtain the sertraline hydrochloride direct-acting granules.

7. The method for preparing sertraline hydrochloride direct-acting granules according to claim 6, characterized in that, In step S1, a portion of the adhesive in the prescription is used to prepare an adhesive aqueous solution with a mass concentration of 3% to 10%, and the remaining adhesive in the prescription is dry-mixed with sertraline hydrochloride, diluent, and disintegrant. In step S1, during mixing, the stirring paddle speed is set to 3. 6r / s, cutting blade speed 25 35 r / s; The dry mixing time is 3 to 10 minutes; the adhesive aqueous solution is added within the first 2 to 4 minutes of dry mixing.

8. The method for preparing sertraline hydrochloride direct-acting granules according to claim 6, characterized in that, In step S1, wet granules are obtained by extrusion spheronization, with the extrusion speed set to 10~50 rpm; after extrusion, a shot blasting step is also included, with the shot blasting speed set to 500~1000 rpm and the time set to 20~80 s.

9. The method for preparing sertraline hydrochloride direct-acting granules according to claim 6, characterized in that, In step S2, the coating parameters are set as follows: outlet air temperature is 20~60℃, inlet air temperature is 20~80℃, atomization pressure is 0.1~0.4 MPa, and material temperature is 30~50℃.

10. The method for preparing sertraline hydrochloride direct-acting granules according to claim 6, characterized in that, In step S3, the mixing speed is set to 5~15 r / min and the mixing time is set to 2~10 min.

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