Fluvoxamine maleate sustained-release capsule and preparation method thereof

Abstract

The invention relates to a fluvoxamine maleate sustained-release capsule with stable release degree, the sustained-release capsule content comprises a sustained-release coated pellet, and the sustained-release coated pellet comprises (a) a blank pellet core, (b) a drug coating layer wrapping the blank pellet core, and (c) a sustained-release coating layer wrapping the drug coating layer. (c) a stable release coating layer wrapping the drug coating layer; and (d) a slow release coating layer wrapping the stable release coating layer. The stable release coating layer comprises a first stable release material and a second stable release material, and the first stable release material is selected from one or more of hydroxypropyl methylcellulose, hydroxy propyl cellulose and povidone. The fluvoxamine maleate sustained-release capsule disclosed by the invention has high-stability in-vitro release degree, small in-batch release degree variation, high in-batch release degree reproducibility and excellent clinical use safety and robustness.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical preparations, in particular to a sustained-release fluvoxamine maleate capsule and a preparation method thereof. BACKGROUND

[0002] Fluvoxamine maleate is a selective serotonin (5-HT) reuptake inhibitor, and its mechanism of action is to inhibit the reuptake of serotonin in brain neurons by specifically inhibiting the transport protein of serotonin reuptake. Fluvoxamine maleate is a commonly used drug in the clinical treatment of obsessive-compulsive disorder, anxiety disorder and depression. However, the ordinary dosage form of fluvoxamine maleate usually needs to be taken several times a day to maintain the effective concentration of the drug in the body, which leads to the problem of patient compliance, which is particularly prominent in long-term treatment.

[0003] Generally, stable release of pharmaceutical preparations can provide stable and sustained effective blood drug concentration, avoid or reduce peak and valley fluctuations, ensure drug safety, and minimize drug side effects or adverse reactions. In the inventors' previous studies, it was found that the drug release of existing sustained-release fluvoxamine maleate capsules had large differences within and between batches. Therefore, it is an urgent technical problem to be solved in the clinic to find a sustained-release fluvoxamine maleate preparation with stable release and good patient compliance. SUMMARY

[0004] To solve the above technical problems, the present application includes the following aspects: The first aspect of the present application provides a sustained-release fluvoxamine maleate capsule with stable release, wherein the content of the sustained-release capsule comprises sustained-release coated pellets, and the sustained-release coated pellets comprise: (a) a blank pellet core, (b) a drug coating layer wrapped outside the blank pellet core, (c) a stable release coating layer wrapped outside the drug coating layer, and (d) a sustained-release coating layer wrapped outside the stable release coating layer; the stable release coating layer comprises a first stable release material and a second stable release material, and the first stable release material is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose and povidone.

[0005] Preferably, the blank pellet core is selected from one or more of sucrose, starch, lactose and microcrystalline cellulose. More preferably, the blank pellet core material is selected from one or more of sucrose and starch. Further preferably, the blank pellet core is a sucrose pellet core.

[0006] Preferably, the weight percentage of the blank pellet core in the content of the sustained-release capsule is 15-30%. More preferably, the weight percentage of the blank pellet core in the content of the sustained-release capsule is 20-26%. Further preferably, the weight percentage of the blank pellet core in the content of the sustained-release capsule is 25.8%.

[0007] Preferably, the drug coating layer comprises fluvoxamine maleate and a binder.

[0008] Preferably, the fluvoxamine maleate is present in the extended release capsule content in an amount of 40-55% by weight. More preferably, the fluvoxamine maleate is present in the extended release capsule content in an amount of 45-50% by weight. Further preferably, the fluvoxamine maleate is present in the extended release capsule content in an amount of 48.4% by weight.

[0009] Preferably, the binder is selected from one or more of hypromellose, hydroxypropyl cellulose. More preferably, the binder is hypromellose. Further preferably, the binder is hypromellose E5.

[0010] Preferably, the binder is present in the extended release capsule content in an amount of 2-10% by weight. More preferably, the binder is present in the extended release capsule content in an amount of 5-8% by weight. Further preferably, the binder is present in the extended release capsule content in an amount of 6.5% by weight.

[0011] Preferably, the first stabilizing release material is selected from one or more of hypromellose E5, hydroxypropyl cellulose EXF, and povidone K30. More preferably, the first stabilizing release material is hypromellose E5, hydroxypropyl cellulose EXF, or povidone K30.

[0012] Preferably, the first stabilizing release material is present in the extended release capsule content in an amount of 2-8% by weight. More preferably, the first stabilizing release material is present in the extended release capsule content in an amount of 4-6% by weight. Further preferably, the first stabilizing release material is present in the extended release capsule content in an amount of 4.8% by weight.

[0013] Preferably, the second stabilizing release material is sodium lauryl sulfate.

[0014] Preferably, the second stabilizing release material is present in the extended release capsule content in an amount of 0.5-3% by weight. More preferably, the second stabilizing release material is present in the extended release capsule content in an amount of 1-2% by weight. Further preferably, the second stabilizing release material is present in the extended release capsule content in an amount of 1.6% by weight.

[0015] Preferably, the first stabilizing release material and the second stabilizing release material are present in a weight ratio of 1:1-5:1. More preferably, the first stabilizing release material and the second stabilizing release material are present in a weight ratio of 2:1-4:1. Further preferably, the first stabilizing release material and the second stabilizing release material are present in a weight ratio of 3:1.

[0016] Preferably, the sustained release coating layer comprises a sustained release material, a sustained release modifying material and a plasticizer.

[0017] Preferably, the sustained release material is selected from one or more of ethyl cellulose, acrylic resin, cellulose acetate. More preferably, the sustained release material is selected from one or more of ethyl cellulose, acrylic resin. Further preferably, the sustained release material is ethyl cellulose N10 or Eudragit RS.

[0018] Preferably, the sustained release material is present in the sustained release capsule content in a weight percentage of 4-12%. More preferably, the sustained release material is present in the sustained release capsule content in a weight percentage of 6-10%. Further preferably, the sustained release material is present in the sustained release capsule content in a weight percentage of 7.9%.

[0019] Preferably, the release modifying material is hydroxypropyl cellulose. More preferably, the release modifying material is hydroxypropyl cellulose EXF.

[0020] Preferably, the release modifying material is present in the sustained release capsule content in a weight percentage of 1-5%. More preferably, the release modifying material is present in the sustained release capsule content in a weight percentage of 2-3%. Further preferably, the release modifying material is present in the sustained release capsule content in a weight percentage of 2.4%.

[0021] Preferably, the plasticizer is selected from one or more of triethyl citrate, diethyl phthalate, dibutyl sebacate. More preferably, the plasticizer is selected from one or more of triethyl citrate, diethyl phthalate. Further preferably, the plasticizer is triethyl citrate.

[0022] Preferably, the plasticizer is present in the sustained release capsule content in a weight percentage of 0.5-2.5%. More preferably, the plasticizer is present in the sustained release capsule content in a weight percentage of 1-2%. Further preferably, the plasticizer is present in the sustained release capsule content in a weight percentage of 1.8%.

[0023] Preferably, the content of the sustained release capsule further comprises a lubricant.

[0024] Preferably, the lubricant is selected from one or more of talc, colloidal silicon dioxide and magnesium stearate. More preferably, the lubricant is selected from one or more of talc, magnesium stearate. Further preferably, the lubricant is talc.

[0025] Preferably, the lubricant is present in the sustained release capsule content in a weight percentage of 0.2-2%. More preferably, the lubricant is present in the sustained release capsule content in a weight percentage of 0.5-1%. Further preferably, the lubricant is present in the sustained release capsule content in a weight percentage of 0.8%.

[0026] Preferably, the sustained release capsule comprises 48.4% fluvoxamine maleate, 25.8% sucrose pellet core, 6.5% hypromellose E5 (binder), 4.8% hypromellose E5 (first sustained release material), 1.6% sodium lauryl sulfate, 7.9% ethyl cellulose N10, 2.4% hydroxypropyl cellulose EXF (sustained release regulating material), 1.8% triethyl citrate and 0.8% talc, all in percentage by weight.

[0027] Preferably, the sustained release capsule comprises 48.4% fluvoxamine maleate, 25.8% sucrose pellet core, 6.5% hypromellose E5 (binder), 4.8% hydroxypropyl cellulose EXF (first sustained release material), 1.6% sodium lauryl sulfate, 7.9% ethyl cellulose N10, 2.4% hydroxypropyl cellulose EXF (sustained release regulating material), 1.8% triethyl citrate and 0.8% talc, all in percentage by weight.

[0028] Preferably, the sustained release capsule comprises 48.4% fluvoxamine maleate, 25.8% sucrose pellet core, 6.5% hypromellose E5 (binder), 4.8% povidone K30 (first sustained release material), 1.6% sodium lauryl sulfate, 7.9% ethyl cellulose N10, 2.4% hydroxypropyl cellulose EXF (sustained release regulating material), 1.8% triethyl citrate and 0.8% talc, all in percentage by weight.

[0029] Preferably, the release profiles of different batches of the sustained release capsule have a similarity factor f2 greater than 60, or greater than 65, or greater than 70, or greater than 75, or greater than 80, or greater than 85, or greater than 90, or greater than 95.

[0030] Preferably, the intra-batch RSD value of the sustained release capsule of the same batch at a specific time point of the in-vitro dissolution test is less than 30%, or less than 25%, or less than 20%, or less than 15%, or less than 10%, or less than 5%.

[0031] Preferably, the specific time point of the in-vitro dissolution test is the 1st hour, or the 2nd hour, or the 3rd hour, or the 4th hour, or the 6th hour, or the 8th hour.

[0032] Preferably, the intra-batch RSD value is the RSD value of 10 samples, or 9 samples, or 8 samples, or 7 samples, or 6 samples, or 5 samples, or 4 samples, or 3 samples of the same batch.

[0033] Preferably, the method for determining the in-vitro dissolution rate of the sustained release capsule is as follows: paddle method, dissolution medium is pH 6.8 phosphate buffer solution, the volume of the dissolution medium is 900 mL, and the detection wavelength is UV 254 nm.

[0034] The second aspect of the present application provides a preparation method of the above-mentioned sustained release capsule of fluvoxamine maleate, which comprises the following steps: 1) dissolving a prescribed amount of a binder in purified water to prepare a binder aqueous solution, and then dispersing a prescribed amount of fluvoxamine maleate in the binder aqueous solution to prepare a drug-containing coating solution; 2) placing a prescribed amount of a blank pellet core in a fluidized bed coating machine, slowly spraying the drug-containing coating solution prepared in step 1) into the fluidized bed, and allowing the blank pellet core to be coated with a drug coating layer to prepare a drug-containing pellet after drying; 3) dissolving a prescribed amount of a first sustained release material and a second sustained release material in purified water to prepare a sustained release coating solution; 4) slowly spraying the sustained release coating solution prepared in step 3) into the fluidized bed, and allowing the drug-containing pellet obtained in step 2) to be coated with a sustained release coating layer to prepare a sustained release coating pellet; 5) dissolving a prescribed amount of a sustained release material, a sustained release adjusting material and a plasticizer in an organic solvent to prepare a sustained release coating solution; 6) slowly spraying the sustained release coating solution prepared in step 5) into the fluidized bed, and allowing the sustained release coating pellet obtained in step 4) to be coated with a sustained release coating layer to prepare a sustained release coating pellet; 7) drying the sustained release coating pellet prepared in step 6) in the fluidized bed; 8) mixing the sustained release pellet prepared in step 7) with a lubricant, and filling the mixture into a capsule to obtain the sustained release capsule of fluvoxamine maleate.

[0035] Preferably, the weight ratio of the active drug to purified water in step 1) is (10-30): 100. More preferably, the weight ratio of the active drug to purified water in step 1) is (15-25): 100. Further preferably, the weight ratio of the active drug to purified water in step 1) is 20: 100.

[0036] Preferably, the fluidized bed coating parameters in step 2) are as follows: the inlet air temperature is 45°C, the material temperature is 40°C, the atomization pressure is 1.5 bar, the air volume is 120 cfm, the humidity is not more than 20%, and the flow rate is 10-20 g / min.

[0037] Preferably, the weight ratio of the combination of the two stabilizing release materials to purified water in step 3) is (1-10): 100. More preferably, the weight ratio of the combination of the two stabilizing release materials to purified water in step 3) is (4-8): 100. Further preferably, the weight ratio of the combination of the two stabilizing release materials to purified water in step 3) is 6: 100.

[0038] Preferably, the fluidized bed coating parameters in step 4) are set as follows: inlet air temperature is 43°C, material temperature is 38°C, atomization pressure is 1.2 bar, air volume is 120 cfm, humidity is no more than 20%, and flow rate is 8-16 g / min.

[0039] Preferably, the organic solvent in step 5) is ethanol.

[0040] Preferably, the weight ratio of the combination of the sustained release material, the sustained release adjusting material and the plasticizer to the organic solvent in step 5) is (1-15): 100. More preferably, the weight ratio of the combination of the sustained release material, the sustained release adjusting material and the plasticizer to the organic solvent in step 5) is (6-10): 100. Further preferably, the weight ratio of the combination of the sustained release material, the sustained release adjusting material and the plasticizer to the organic solvent in step 5) is 8: 100.

[0041] Preferably, the fluidized bed coating parameters in step 6) are set as follows: inlet air temperature is 38°C, material temperature is 32°C, atomization pressure is 1.2 bar, air volume is 120 cfm, humidity is 20-40%, and flow rate is 10-20 g / min.

[0042] Preferably, the fluidized bed coating parameters in step 7) are set as follows: inlet air temperature is 50°C, material temperature is 45°C, air volume is 120 cfm, humidity is less than 10%, and drying time is 2 hours.

[0043] The third aspect of the present application provides the use of the above-mentioned fluvoxamine maleate sustained release capsule in the preparation of a medicament for treating obsessive-compulsive disorder, anxiety or depression.

[0044] The fourth aspect of the present application provides a method for improving the release stability of the above-mentioned fluvoxamine maleate sustained release capsule, wherein the content of the sustained release capsule comprises sustained release coated pellets, and the sustained release coated pellets comprise: (a) a blank pellet core, (b) a drug coating layer wrapped outside the blank pellet core, and (d) a sustained release coating layer wrapped outside the drug coating layer; the method comprises adding (c) a stabilizing release coating layer between the drug coating layer and the sustained release coating layer, and the stabilizing release coating layer comprises a first stabilizing release material and a second stabilizing release material, the first stabilizing release material is selected from one or more of hydroxypropyl methyl cellulose, hydroxypropyl cellulose and povidone, and the second stabilizing release material is sodium dodecyl sulfate.

[0045] Preferably, the first stabilizing release material is selected from one or more of Hypromellose E5, Hypromellose EXF and Povidone K30. More preferably, the first stabilizing release material is Hypromellose E5, Hypromellose EXF or Povidone K30.

[0046] Preferably, the weight percentage of the first stabilizing release material in the sustained release capsule content is 2-8%. More preferably, the weight percentage of the first stabilizing release material in the sustained release capsule content is 4-6%. Further preferably, the weight percentage of the first stabilizing release material in the sustained release capsule content is 4.8%.

[0047] Preferably, the weight percentage of the second stabilizing release material in the sustained release capsule content is 0.5-3%. More preferably, the weight percentage of the second stabilizing release material in the sustained release capsule content is 1-2%. Further preferably, the weight percentage of the second stabilizing release material in the sustained release capsule content is 1.6%.

[0048] Preferably, the weight ratio of the first stabilizing release material to the second stabilizing release material is 1:1-5:1. More preferably, the weight ratio of the first stabilizing release material to the second stabilizing release material is 2:1-4:1. Further preferably, the weight ratio of the first stabilizing release material to the second stabilizing release material is 3:1.

[0049] Technical effects of the present application: The maleic acid fluvoxamine sustained release capsule of the present application innovatively adds a stabilizing release coating layer between the drug coating layer and the sustained release coating layer, the stabilizing release coating layer comprising a first stabilizing release material (hypromellose, hydroxypropyl cellulose or povidone) and a second stabilizing release material (sodium dodecyl sulfate). By setting the above stabilizing release coating layer, the maleic acid fluvoxamine sustained release capsule of the present application has a highly stable in vitro release rate, a small batch release rate variation, a high batch release rate reproducibility, and excellent clinical use safety and robustness. DETAILED DESCRIPTION

[0050] Test Example 1, in vitro release rate test of commercially available maleic acid fluvoxamine sustained release capsules 1. Test method Three different batches of commercially available fluvoxamine maleate sustained-release capsules (purchased from ACTAVIS, specification 150 mg) were selected, the paddle method was used to determine the release rate of the sustained-release capsules, the dissolution medium was pH 6.8 phosphate buffer solution, the volume of the dissolution medium was 900 mL, 6 parallel samples were taken at 1 h, 2 h, 3 h, 4 h, 6 h and 8 h, respectively, the release rate (%) of fluvoxamine maleate of different samples at each sampling time point was determined, and the detection wavelength was UV 254 nm. The average release rate data (%) of different samples of each batch and the RSD data (%) between samples and the similarity factor f2 value between different batches were calculated.

[0051] 2. Test results The release rate results of three batches of commercially available fluvoxamine maleate sustained-release capsules are shown in Table 1 below.

[0052] Table 1 Release rate (%) of commercially available fluvoxamine maleate sustained-release capsules

[0053] As shown in Table 1 above, the average release rate similarity factor f2 between the three batches of commercially available fluvoxamine maleate sustained-release capsules is not greater than 60, and the similarity of the release behavior between batches is poor. In addition, the release rate difference between different samples in the same batch is also large, especially the release rate deviation RSD value of different samples in the early release period (1 h and 2 h) is greater than 15%. The above test results confirm that the drug release rate of commercially available fluvoxamine maleate sustained-release capsules has large differences between batches and within batches, and such release rate difference will lead to the fact that the drug preparation cannot provide stable blood drug concentration after being taken, and the drug peak and valley fluctuation occurs, thereby increasing the side effects of the drug and the safety of clinical drug use.

[0054] Test Example 2, in vitro release rate test of fluvoxamine maleate sustained-release capsules of the present application 1. Test method 1.1. Preparation of sustained-release capsules (1) Formulation and preparation method of Examples 1-3 The formulations of Examples 1-3 of the present application are shown in the table below (the unit dose drug content is 150 mg, and each auxiliary material unit is mg).

[0055]

[0056] The preparation method of Examples 1-3 is as follows: 1) Dissolve the prescription amount of adhesive in purified water to prepare an adhesive aqueous solution, then disperse the prescription amount of fluvoxamine maleate in the adhesive aqueous solution to prepare a drug-containing coating solution, wherein the weight ratio of active drug to purified water is 20:100; 2) Put the prescribed amount of blank pellet core into the fluidized bed coating machine, slowly spray the drug-containing coating solution prepared in step 1) into the fluidized bed, so that the blank pellet core is coated with a drug-containing coating layer, and after drying, the drug-containing pellets are prepared; The fluidized bed coating parameters of this step are set as follows: inlet air temperature is 45℃, material temperature is 40℃, atomization pressure is 1.5 bar, air volume is 120 cfm, humidity is not more than 20%, and flow rate is 10-20 g / min; 3) Dissolve the prescribed amount of the first and second stable release materials in purified water to prepare a stable release coating solution, wherein the weight ratio of the combination of the two stable release materials to purified water is 6:100; 4) Slowly spray the stable release coating solution prepared in step 3) into the fluidized bed, so that the drug-containing pellets obtained in step 2) are coated with a stable release coating layer, to prepare stable release coated pellets; The fluidized bed coating parameters of this step are set as follows: inlet air temperature is 43℃, material temperature is 38℃, atomization pressure is 1.2 bar, air volume is 120 cfm, humidity is not more than 20%, and flow rate is 8-16 g / min; 5) Dissolve the prescribed amount of the sustained release material, the sustained release adjusting material and the plasticizer in ethanol to prepare a sustained release coating solution, wherein the weight ratio of the combination of the sustained release material, the sustained release adjusting material and the plasticizer to ethanol is 8:100; 6) Slowly spray the sustained release coating solution prepared in step 5) into the fluidized bed, so that the stable release coated pellets obtained in step 4) are coated with a sustained release coating layer, to prepare sustained release coated pellets; The fluidized bed coating parameters of this step are set as follows: inlet air temperature is 38℃, material temperature is 32℃, atomization pressure is 1.2 bar, air volume is 120 cfm, humidity is 20-40%, and flow rate is 10-20 g / min; 7) Dry the sustained release coated pellets prepared in step 6) in the fluidized bed; the fluidized bed coating parameters of this step are set as follows: inlet air temperature is 50℃, material temperature is 45℃, air volume is 120 cfm, humidity is less than 10%, and drying time is 2 hours.

[0057] 8) Mix the sustained release pellets prepared in step 7) with the lubricant, and fill into capsules to obtain the product.

[0058] The amount of fluvoxamine maleate in each batch is 900 g, and the amount of the remaining excipients is calculated according to the prescription unit dose.

[0059] (2) Formulation and preparation method of Comparative Example 1-2 The formulation of the present application Comparative Example 1-2 is shown in the following table (the unit dose of the drug is 150 mg, and each excipient is mg).

[0060]

[0061] The preparation method of Comparative Example 1-2 is as follows: 1) Dissolve the prescribed amount of the binder in purified water to prepare a binder aqueous solution, and then disperse the prescribed amount of fluvoxamine maleate in the binder aqueous solution to prepare a drug-containing coating solution, wherein the weight ratio of the active drug to purified water is 20:100; 2) Place the prescribed amount of the blank pellet core in the fluidized bed coating machine, and slowly spray the drug-containing coating solution prepared in step 1) into the fluidized bed to coat the blank pellet core with a drug coating layer, and after drying, obtain the drug-containing pellets; The fluidized bed coating parameters of this step are as follows: the inlet air temperature is 45°C, the material temperature is 40°C, the atomization pressure is 1.5 bar, the air volume is 120 cfm, the humidity is not more than 20%, and the flow rate is 10-20 g / min; 3) Dissolve the prescribed amount of the sustained-release material, the sustained-release adjusting material, and the plasticizer in ethanol to prepare a sustained-release coating solution, wherein the weight ratio of the combination of the sustained-release material, the sustained-release adjusting material, and the plasticizer to ethanol is 8:100; 4) Slowly spray the sustained-release coating solution prepared in step 3) into the fluidized bed to coat the drug-containing pellets obtained in step 2) with a sustained-release coating layer to obtain the sustained-release coated pellets; The fluidized bed coating parameters of this step are as follows: the inlet air temperature is 38°C, the material temperature is 32°C, the atomization pressure is 1.2 bar, the air volume is 120 cfm, the humidity is 20-40%, and the flow rate is 10-20 g / min; 5) Dry the sustained-release coated pellets prepared in step 4) in the fluidized bed; the fluidized bed coating parameters of this step are as follows: the inlet air temperature is 50°C, the material temperature is 45°C, the air volume is 120 cfm, the humidity is less than 10%, and the drying time is 2 hours; 6) Mix the sustained-release pellets prepared in step 5) with the lubricant, and fill them into capsules to obtain the product.

[0062] The amount of fluvoxamine maleate in each batch is 900 g, and the amount of the remaining excipients is calculated according to the prescription unit dose.

[0063] (3) Formulation and preparation method of Comparative Examples 3-5 The formulations of Comparative Examples 3-5 of the present application are shown in the following table (the unit dose of the drug is 150 mg, and each excipient is in mg).

[0064]

[0065] The preparation method of Comparative Examples 3-5 is as follows: 1) Dissolve a prescribed amount of binder in purified water to prepare a binder solution, then disperse a prescribed amount of fluvoxamine maleate in the binder solution to prepare a drug-containing coating solution, wherein the weight ratio of active drug to purified water is 20:100; 2) Place a prescribed amount of blank pellet cores in a fluidized bed coater, slowly spray the drug-containing coating solution prepared in step 1) into the fluidized bed, and coat the blank pellet cores with a drug coating layer to prepare drug-containing pellets after drying; The fluidized bed coating parameters of this step are set as follows: inlet air temperature is 45°C, material temperature is 40°C, atomization pressure is 1.5 bar, air volume is 120 cfm, humidity is not more than 20%, and flow rate is 10-20 g / min; 3) Dissolve a prescribed amount of first sustained release material in purified water to prepare a sustained release coating solution, wherein the weight ratio of first sustained release material to purified water is 6:100; 4) Slowly spray the sustained release coating solution prepared in step 3) into the fluidized bed to coat the drug-containing pellets obtained in step 2) with a sustained release coating layer to prepare sustained release coated pellets; The fluidized bed coating parameters of this step are set as follows: inlet air temperature is 43°C, material temperature is 38°C, atomization pressure is 1.2 bar, air volume is 120 cfm, humidity is not more than 20%, and flow rate is 8-16 g / min; 5) Dissolve a prescribed amount of sustained release material, sustained release adjusting material, and plasticizer in ethanol to prepare a sustained release coating solution, wherein the weight ratio of the combination of sustained release material, sustained release adjusting material, and plasticizer to ethanol is 8:100; 6) Slowly spray the sustained release coating solution prepared in step 5) into the fluidized bed to coat the sustained release coated pellets obtained in step 4) with a sustained release coating layer to prepare sustained release coated pellets; The fluidized bed coating parameters of this step are set as follows: inlet air temperature is 38°C, material temperature is 32°C, atomization pressure is 1.2 bar, air volume is 120 cfm, humidity is 20-40%, and flow rate is 10-20 g / min; 7) Dry the sustained release coated pellets prepared in step 6) in a fluidized bed; the fluidized bed coating parameters of this step are set as follows: inlet air temperature is 50°C, material temperature is 45°C, air volume is 120 cfm, humidity is less than 10%, and drying time is 2 hours.

[0066] 8) Mix the sustained release pellets prepared in step 7) with a lubricant, and fill into capsules to obtain the final product.

[0067] The amount of fluvoxamine maleate used in each batch is 900 g, and the amounts of other excipients are calculated based on the unit dose.

[0068] (4) Formulation and preparation method of Comparative Example 6-7 The formulation of Comparative Example 6-7 of the present application is shown in the following table (the unit dose drug content is 150 mg, and each auxiliary material unit is mg).

[0069]

[0070] The preparation method of Comparative Example 6-7 is as follows: 1) Dissolve the prescription amount of adhesive and the second sustained release material in purified water to prepare an adhesive aqueous solution, and then disperse the prescription amount of fluvoxamine maleate in the adhesive aqueous solution to prepare a drug-containing coating solution, wherein the weight ratio of active drug to purified water is 20:100; 2) Place the prescription amount of blank pellet cores in a fluidized bed coating machine, slowly spray the drug-containing coating solution prepared in step 1) into the fluidized bed, and coat the blank pellet cores with a drug coating layer, and after drying, obtain drug-containing pellets; The fluidized bed coating parameters of this step are as follows: inlet air temperature is 45°C, material temperature is 40°C, atomization pressure is 1.5 bar, air volume is 120 cfm, humidity is not more than 20%, and flow rate is 10-20 g / min; 3) Dissolve the prescription amount of sustained release material, sustained release adjusting material and plasticizer in ethanol to prepare a sustained release coating solution, wherein the weight ratio of the combination of sustained release material, sustained release adjusting material and plasticizer to ethanol is 8:100; 4) Slowly spray the sustained release coating solution prepared in step 3) into the fluidized bed to coat the drug-containing pellets obtained in step 2) with a sustained release coating layer to obtain sustained release coated pellets; The fluidized bed coating parameters of this step are as follows: inlet air temperature is 38°C, material temperature is 32°C, atomization pressure is 1.2 bar, air volume is 120 cfm, humidity is 20-40%, and flow rate is 10-20 g / min; 5) Dry the sustained release coated pellets prepared in step 4) in a fluidized bed; the fluidized bed coating parameters of this step are as follows: inlet air temperature is 50°C, material temperature is 45°C, air volume is 120 cfm, humidity is less than 10%, and drying time is 2 hours.

[0071] 6) Mix the sustained release pellets prepared in step 5) with a lubricant, and fill it into a capsule to obtain the sustained release capsule.

[0072] The amount of fluvoxamine maleate in each batch is 900 g, and the amount of the remaining auxiliary materials is calculated according to the prescription unit dose.

[0073] 1.2, dissolution test of sustained release capsules The release degree of the sustained-release capsules of Examples 1-3 and Comparative Examples 1-7 was determined by the paddle method, the dissolution medium was pH 6.8 phosphate buffer solution, the volume of the dissolution medium was 900 mL, samples were taken at 1 h, 2 h, 3 h, 4 h, 6 h and 8 h, respectively, 3 batches of samples were taken for Examples 1-3, 1 batch of sample was taken for Comparative Examples 1-7, 6 parallel samples were taken for each batch of each example or comparative example, the release degree (%) of fluvoxamine maleate of different samples of each example and comparative example at each sampling time point was determined, the detection wavelength was UV 254 nm. The average release degree data (%) of different samples of each example and comparative example, the RSD data (%) between samples and the batch-to-batch similarity factor f2 value of the examples were calculated.

[0074] 2. Test results The release degree results of the fluvoxamine maleate sustained-release capsules of Examples 1-3 of the present application are shown in Table 2 below.

[0075] Table 2 Release degree (%) of fluvoxamine maleate sustained-release capsules of Examples 1-3

[0076] The release degree results of the fluvoxamine maleate sustained-release capsules of Comparative Examples 1-2 of the present application are shown in Table 3 below.

[0077] Table 3 Release degree (%) of fluvoxamine maleate sustained-release capsules of Comparative Examples 1-2

[0078] The release degree results of the fluvoxamine maleate sustained-release capsules of Comparative Examples 3-5 of the present application are shown in Table 4 below.

[0079] Table 4 Release degree (%) of fluvoxamine maleate sustained-release capsules of Comparative Examples 3-5

[0080] The release degree results of the fluvoxamine maleate sustained-release capsules of Comparative Examples 6-7 of the present application are shown in Table 5 below.

[0081] Table 5 Release degree (%) of fluvoxamine maleate sustained-release capsules of Comparative Examples 6-7

[0082] As shown in Table 2 above, the fluvoxamine maleate sustained-release capsules of Examples 1-3 of the present application achieved more stable batch-to-batch and intra-batch release by innovatively adding a stable release layer (including a first stable release material and a second stable release material) between the drug coating layer and the sustained-release coating layer, wherein the batch-to-batch dissolution release similarity factor f2 of Examples 1-3 were all greater than 78, and the intra-batch sample release RSD values were all less than 19%. In contrast, the fluvoxamine maleate sustained-release capsules of Comparative Examples 1-2 (similar to the composition of the ACTAVIS commercial preparation) did not contain a stable release layer, and the intra-batch sample release RSD value at 1 hour was greater than 28% (see Table 3), the fluvoxamine maleate sustained-release capsules of Comparative Examples 3-5 did not contain a second stable release material, and the intra-batch sample release RSD value at 1 hour was greater than 26% (see Table 4), and the fluvoxamine maleate sustained-release capsules of Comparative Examples 6-7 did not contain a first stable release material, and the intra-batch sample release RSD values at 1 hour and 2 hours were greater than 45% and 22%, respectively (see Table 5). The above comparative test results show that the fluvoxamine maleate sustained-release capsules of the present application with the innovative structure have highly stable in-vitro release, small intra-batch release variability, and high batch-to-batch release reproducibility, and have excellent clinical use safety and robustness.

[0083] While particular embodiments of the present application have been described, alternatives, modifications, equivalents, and improvements encouraged by the practice of the present application are possible. Accordingly, the present application intends to embrace all such alternatives, modifications, equivalents, and improvements that fall within the scope of the appended claims and their equivalents.

Claims

1. A sustained-release capsule for fluvoxamine maleate with stable release, characterized in that, The sustained-release capsule contents comprise sustained-release coated microspheres, each of which comprises: (a) a blank core, (b) a drug coating layer surrounding the blank core, (c) a stable-release coating layer surrounding the drug coating layer, and (d) a sustained-release coating layer surrounding the stable-release coating layer; the stable-release coating layer comprises a first stable-release material and a second stable-release material, wherein the first stable-release material is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and povidone.

2. The sustained-release capsule according to claim 1, characterized in that, The first stable release material is selected from one or more of hydroxypropyl methylcellulose E5, hydroxypropyl cellulose EXF, and povidone K30.

3. The sustained-release capsule according to claim 1, characterized in that, The second stable release material is sodium dodecyl sulfate.

4. The sustained-release capsule according to claim 1, characterized in that, The weight ratio of the first stable release material to the second stable release material is 1:1 to 5:

1.

5. The sustained-release capsule according to claim 1, characterized in that, The drug coating layer contains fluvoxamine maleate and an adhesive.

6. The sustained-release capsule according to claim 1, characterized in that, The sustained-release coating layer comprises a sustained-release material, a sustained-release modifier, and a plasticizer.

7. The sustained-release capsule according to claim 1, characterized in that, The release similarity factor f2 of the sustained-release capsules from different batches is greater than 60.

8. The method for preparing fluvoxamine maleate sustained-release capsules according to any one of claims 1-7, characterized in that, The method includes the following steps: 1) Dissolve the prescribed amount of adhesive in purified water to prepare an adhesive aqueous solution, and then disperse the prescribed amount of fluvoxamine maleate in the adhesive aqueous solution to prepare a drug-coated solution; 2) Place the prescribed amount of blank pellet cores into a fluidized bed coating machine, and slowly spray the drug-containing coating solution prepared in step 1) into the fluidized bed so that the blank pellet cores are coated with a drug coating layer. After drying, drug-containing micro pellets are prepared. 3) Dissolve the prescribed amounts of the first and second stable-release materials in purified water to prepare a stable-release coating solution; 4) The stable release coating solution prepared in step 3) is slowly sprayed into the fluidized bed so that the drug-containing microspheres obtained in step 2) are coated with a stable release coating layer to prepare stable release coated microspheres. 5) Dissolve the prescribed amount of sustained-release material, sustained-release modifier and plasticizer in an organic solvent to prepare a sustained-release coating solution; 6) The sustained-release coating solution prepared in step 5) is slowly sprayed into the fluidized bed so that the stable-release coated microspheres obtained in step 4) are coated with a sustained-release coating layer to prepare sustained-release coated microspheres. 7) Dry the sustained-release coated microspheres obtained in step 6) in a fluidized bed; 8) Mix the sustained-release microspheres prepared in step 7) with a lubricant and fill them into capsules to obtain the final product.

9. The use of the fluvoxamine maleate sustained-release capsules according to any one of claims 1-7 in the preparation of a medicament for treating obsessive-compulsive disorder, anxiety disorder or depression.

10. A method for improving the release stability of the above-mentioned fluvoxamine maleate sustained-release capsules, characterized in that, The sustained-release capsule contents comprise sustained-release coated microspheres, each microsphere comprising: (a) a blank core, (b) a drug coating layer surrounding the blank core, and (d) a sustained-release coating layer surrounding the drug coating layer; the method comprises adding (c) a stable-release coating layer between the drug coating layer and the sustained-release coating layer, the stable-release coating layer comprising a first stable-release material and a second stable-release material, wherein the first stable-release material is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and povidone, and the second stable-release material is sodium dodecyl sulfate.

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