Fluoxetine hydrochloride long-acting tablet and preparation method thereof

Abstract

The fluoxetine hydrochloride long-acting tablet comprises a tablet core, a common film coating layer and an enteric coating layer, and is specifically characterized in that (1) the tablet core comprises a solid dispersion prepared from fluoxetine hydrochloride and hydroxypropyl methylcellulose acetate succinate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, lactose, pregelatinized starch and magnesium stearate; (2) the common film coating layer contains hydroxypropyl methyl cellulose and succinic acid; (3) the enteric coating layer is composed of enteric acrylic resin, sodium alginate, soluble calcium salt CaCl2, glycerin and talcum powder, and the invention discloses a preparation method of the fluoxetine hydrochloride long-acting tablet, the fluoxetine hydrochloride long-acting tablet prepared by the invention can reduce the administration frequency, improve the medication safety, better meet the medication requirement, meet the depression remission period and improve the bioavailability of the fluoxetine hydrochloride long-acting tablet. And the drug can be used for consolidation period treatment or maintenance period treatment, and has very important clinical value.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical preparations, and specifically provides a fluoxetine hydrochloride long-acting tablet and a preparation method thereof. BACKGROUND

[0002] The chemical formula of fluoxetine hydrochloride is C 17 H 19 ClF3NO, with a molecular weight of 345.787 and a CAS number of 59333-67-4, is a selective 5-HT reuptake inhibitor (SSRI) widely used in clinical practice. It selectively inhibits the 5-HT transporter, blocks the reuptake of 5-HT at the presynaptic membrane, prolongs and increases the action of 5-HT, and thus produces an antidepressant effect. It has low affinity for adrenergic, histaminergic, and cholinergic receptors, and weak effects, thus producing fewer adverse reactions. It is well absorbed after oral administration, with a bioavailability of 70%, and easily passes through the blood-brain barrier. A small amount can also be secreted into breast milk. It is metabolized in the liver by CYP2D6 to produce nortriptyline, which also has an antidepressant effect. The product is a white or white-like crystalline powder, odorless, easily soluble in methanol or ethanol, slightly soluble in water or chloroform, and insoluble in diethyl ether. The current pharmaceutical dosage forms of fluoxetine include solutions, dispersible tablets, ordinary tablets, capsules, sustained-release capsules, and sustained-release tablets.

[0003] CN112741819B discloses a fluoxetine hydrochloride capsule and a preparation method thereof, and application in quality and efficacy consistency evaluation thereof. The fluoxetine hydrochloride is crushed, and the excipients are sieved. Dimethicone emulsion is sprayed onto the surface of pregelatinized starch to obtain pregelatinized starch blank granules by granulation. The pregelatinized starch blank granules are mixed with fluoxetine hydrochloride, pregelatinized starch, and silicon dioxide, and then filled into capsules, and aluminum plastic packaged to obtain the fluoxetine hydrochloride capsule. The content, content uniformity, related substances, and dissolution of the prepared fluoxetine hydrochloride capsule are consistent with those of the reference preparation (fluoxetine hydrochloride capsule, Prozac, 20 mg, licensed merchant LILLY FRANCE). The in vitro dissolution curves are similar to those of the reference preparation. The product is bioequivalent to the reference preparation, has good safety and compliance, and has good stability for 24 months without increasing the packaging cost. However, dimethicone itself has a slight oily odor and taste. In oral preparations, even after flavoring treatment, some patients can still feel the greasy feeling, affecting medication compliance. Dimethicone has high viscosity and is insoluble in water, making it very difficult to uniformly disperse in liquid preparations to form a stable emulsion, usually requiring high-shear homogenization equipment and suitable emulsifiers, increasing the complexity and cost of the process.

[0004] CN116172970A provides a long-acting fluoxetine hydrochloride tablet and its preparation method. The long-acting fluoxetine tablet includes a tablet core, a common film coating layer, and an enteric coating layer. Compared with the prior art, the new high-specification fluoxetine tablet provided by this invention is easy to prepare and maintains the integrity of the enteric coating, improving drug release. Furthermore, the tablet does not contain Tween-80, allowing for once-weekly dosing with advantages such as low dosing frequency and fewer side effects. The tablet core comprises a tablet core, a common film coating layer, and an enteric coating layer. The tablet core is composed of fluoxetine or its acid salt and pharmaceutically acceptable excipients, specifically fluoxetine or its acid salt, microcrystalline cellulose, hydroxypropyl cellulose, lactose, hydroxypropyl methylcellulose, magnesium stearate, and polyvinylpyrrolidone. The common film coating layer is hydroxypropyl methylcellulose. The enteric coating layer is composed of acrylic resin, triethyl citrate, polyethylene glycol, mannitol, and talc. The enteric coating layer contains polyethylene glycol, which is water-soluble. In the acidic environment of the stomach, even if the enteric polymer does not dissolve, polyethylene glycol will partially dissolve or swell by absorbing water, forming micropores or channels in the coating film. Gastric acid and gastric juice can permeate into the tablet core through these channels, causing premature drug release and thus degradation and inactivation.

[0005] Therefore, providing a long-acting oral formulation of fluoxetine can reduce the frequency of administration, improve medication safety, better meet medication needs, meet the needs of depression remission, and be used for consolidation or maintenance treatment, which has very important clinical value. Summary of the Invention

[0006] The purpose of this invention is to provide a long-acting fluoxetine hydrochloride tablet.

[0007] A long-acting fluoxetine hydrochloride tablet includes a tablet core, a common film coating layer, and an enteric coating layer, specifically:

[0008] (1) The core of the tablet comprises a solid dispersion made of fluoxetine hydrochloride and hydroxypropyl methylcellulose acetate succinate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, lactose, pregelatinized starch and magnesium stearate.

[0009] (2) The ordinary film coating layer contains hydroxypropyl methylcellulose and succinic acid;

[0010] (3) The enteric coating layer is composed of enteric acrylic resin, sodium alginate, soluble calcium salt CaCl2, glycerol and talc.

[0011] The long-acting fluoxetine hydrochloride tablet comprises a tablet core, a common film coating layer, and an enteric coating layer, specifically:

[0012] (1) The core of the tablet is prepared from the following raw materials in parts by weight: 9 parts of fluoxetine hydrochloride, 18-36 parts of hydroxypropyl methylcellulose acetate succinate, 5-9 parts of microcrystalline cellulose, 2-4 parts of low-substituted hydroxypropyl cellulose, 2-3 parts of lactose, 1-2 parts of pregelatinized starch and 0.2-0.4 parts of magnesium stearate;

[0013] (2) The ordinary film coating layer is prepared from the following raw materials in parts by weight: 1-3 parts of hydroxypropyl methylcellulose and 0.5-1 parts of succinic acid;

[0014] (3) The enteric coating layer is prepared from the following raw materials in parts by weight: 2-4 parts enteric acrylic resin, 0.1-0.3 parts sodium alginate, 0.075 parts soluble calcium salt, 0.125 parts glycerol and 1-3 parts talc.

[0015] The long-acting fluoxetine hydrochloride tablets include a tablet core, a common film coating layer and an enteric coating layer, specifically: (1) The tablet core is prepared from the following raw materials in parts by weight: 9 parts fluoxetine hydrochloride, 27 parts hydroxypropyl methylcellulose acetate succinate, 7 parts microcrystalline cellulose, 2.8 parts low-substituted hydroxypropyl cellulose, 2.5 parts lactose, 1.5 parts pregelatinized starch and 0.3 parts magnesium stearate;

[0016] (2) The ordinary film coating layer is prepared from the following raw materials in parts by weight: 1.75 parts of hydroxypropyl methylcellulose and 0.75 parts of succinic acid;

[0017] (3) The enteric coating layer is prepared from the following raw materials in parts by weight: 3 parts enteric acrylic resin, 0.2 parts sodium alginate, 0.075 parts soluble calcium salt, 0.125 parts glycerol and 1.6 parts talc.

[0018] The preparation method of the long-acting fluoxetine hydrochloride tablets includes the following steps:

[0019] (1) Weigh fluoxetine hydrochloride and hydroxypropyl methylcellulose succinate, add them to ethanol / water = 80 / 20 (v / v), stir for 30 min until clear, spray dry under the following conditions: feed temperature: 45℃, outlet air temperature: 95℃, feed rate: 5mL / min, to obtain a solid dispersion;

[0020] (2) Mix solid dispersion, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, lactose, and pregelatinized starch to prepare a 5% PVP-K30 aqueous solution. Spray the binder into the mixture while stirring, and continue stirring to form wet soft granules. Dry in a fluidized bed at 45°C for 15 minutes. Granulate the granules with a sieve aperture of 0.8 mm. Add magnesium stearate and mix for 2 minutes. Compress the granules using a rotary tablet press and control the hardness at 100-130 N to obtain tablet cores.

[0021] (3) Ordinary film coating layer: Hydroxypropyl methylcellulose and succinic acid are dissolved in water and heated to 60°C. The spray gun temperature is 50°C. The liquid is sprayed.

[0022] (4) Enteric gel coating layer: a. Take water / ethanol (volume ratio 70:30) solvent, add acrylic resin L100-55 under stirring, stir until uniformly dispersed, add sodium alginate, continue stirring until uniformly dissolved / colloidal, add glycerol and stir evenly; b. Take water to dissolve CaCl2 to prepare a low concentration solution, slowly add it to the solution prepared in step a under stirring to avoid local gel lumps, add talc powder that has been pre-sieved through a 200-mesh sieve to form a uniform suspension system, filter once through an 80-mesh sieve, let stand to remove bubbles, and obtain the coating solution; c. Load the film cores coated with ordinary film layer into the coating pan; preheat to the film bed temperature of 35-40℃, spray, dynamically adjust the air volume, spray speed and angle during the spraying process to avoid film sticking and spray spots; after spraying, continue hot air drying for 10-20 minutes, and finally cool with cold air for 5-10 minutes; check that the enteric layer is intact, undamaged and without obvious spray spots.

[0023] The long-acting fluoxetine hydrochloride tablet comprises a tablet core, a common film coating layer, and an enteric coating layer, wherein the weight gain of the common film coating layer is 3-8% of the weight of the tablet core.

[0024] The fluoxetine hydrochloride long-acting tablet comprises a tablet core, a common film coating layer, and an enteric coating layer, wherein the weight gain of the common film coating layer is 4-6% of the weight of the tablet core.

[0025] The long-acting fluoxetine hydrochloride tablet comprises a tablet core, a common film coating layer, and an enteric coating layer, wherein the weight gain of the enteric coating layer is 6-12% of the weight of the tablet core.

[0026] The long-acting fluoxetine hydrochloride tablet comprises a tablet core, a common film coating layer, and an enteric coating layer, wherein the weight gain of the enteric coating layer is 8-10% of the weight of the tablet core.

[0027] The fluoxetine hydrochloride long-acting tablets include a tablet core, a common film coating layer, and an enteric coating layer. In acid, the release rate is less than 5% within 2 hours; under pH 6.8 conditions, the cumulative release rate is 40-70% over 36-72 hours.

[0028] Fluoxetine hydrochloride is a white or off-white crystalline powder, odorless, readily soluble in methanol or ethanol, slightly soluble in water or chloroform, and insoluble in ether. This invention prepares a solid dispersion by mixing fluoxetine hydrochloride with hydroxypropyl methylcellulose acetate succinate (HPMCAS) in a specific ratio (1:3), resulting in extremely low solubility of the drug in acid and the formation of a stable hydrophobic structure. This structure forms a dense framework with microcrystalline cellulose, hindering initial wetting and diffusion, thereby achieving a drug release of <5% within 2 hours in acid. Succinic acid is added to the ordinary film layer, remaining insoluble under gastric acid conditions, but rapidly swelling to form a hydrophilic layer upon entering the intestinal fluid, gradually exposing the tablet core after entering the intestine and avoiding explosive release. The enteric coating layer uses acrylic resin L100-55-sodium alginate-Ca... 2+ Gel network structure. Sodium alginate in Ca 2+ The presence of cross-linking forms a tight gel network, further delaying drug diffusion and enabling the formulation of this invention to continuously release drugs within 7 days, exhibiting near-zero-order release characteristics. The three structural layers are coupled to each other, forming a multidimensional sustained-release mechanism through "solid dispersion controlled solubility - film layer swelling delay - gel network rate-limiting diffusion," achieving long-term controlled-release characteristics that are significantly different from existing technologies.

[0029] Compared with comparative examples 1-4, the dissolution rate of the present invention is more stable at 36h, 72h, 120h and 168h, and the amount of impurities generated in accelerated stability is reduced by 40-60%, with significantly improved performance, which is an unexpected technical effect.

[0030] According to Table 1 and Figure 1 The experimental results show that the fluoxetine hydrochloride tablets of Examples 1-3 of this invention have stable release. Comparative Example 1 did not use hydroxypropyl methylcellulose acetate succinate in the preparation of the fluoxetine hydrochloride tablets, and Comparative Example 2 did not use microcrystalline cellulose, resulting in insufficient sustained release. Comparative Example 3 did not use succinic acid, and Comparative Example 4 did not use sodium alginate, thus failing to achieve a sustained release effect; however, at 36 hours, 75% of the drug had been released. The experimental results indicate that a specific combination of fluoxetine hydrochloride and hydroxypropyl methylcellulose acetate succinate has a very significant impact on the sustained release of the drug. The best sustained release effect is achieved when the weight ratio of fluoxetine hydrochloride to hydroxypropyl methylcellulose acetate succinate is 1:3 and the weight ratio of fluoxetine hydrochloride to microcrystalline cellulose is 9:7.

[0031] Table 2 shows that, compared with Comparative Examples 1-4, the long-acting fluoxetine hydrochloride tablets of the present invention remained stable in quality after 6 months of accelerated stability testing (conditions: 40℃±2℃ / relative humidity 75%±5%). The tablets were white in appearance, with total impurities not exceeding 0.2%, and the content remained essentially unchanged. Example 1 showed the best effect. Comparative Example 1 did not use hydroxypropyl methylcellulose acetate succinate in the preparation of the fluoxetine hydrochloride tablets. Comparative Example 2 did not use microcrystalline cellulose, thus failing to form a stable solid dispersion. Solid dispersions significantly improve the storage stability of fluoxetine, significantly reduce the delayed disintegration release of degradation products (chlorinated impurities) such as starch, and form a coupled sustained-release structure with the gel membrane. Comparative Example 3 did not use succinic acid. Succinic acid is insoluble in acid but soluble in intestinal fluid, rapidly swelling the film layer. Comparative Example 4 did not use sodium alginate, which cannot form a gel network with calcium chloride (CaCl2). Therefore, the lack of succinic acid and sodium alginate failed to achieve the effect of delaying the degradation of fluoxetine hydrochloride. Attached Figure Description

[0032] Figure 1 The release rate of fluoxetine hydrochloride tablets in artificial intestinal fluid after 2 hours of acid treatment. Detailed Implementation

[0033] Example 1:

[0034] Raw material preparation:

[0035] (1) Tablet core: 90g fluoxetine hydrochloride, 270g hydroxypropyl methylcellulose succinate acetate, 70g microcrystalline cellulose, 28g low-substituted hydroxypropyl cellulose, 25g lactose, 15g pregelatinized starch and 3g magnesium stearate.

[0036] (2) Ordinary film coating layer: 17.5g hydroxypropyl methylcellulose, 7.5g succinic acid;

[0037] (3) Enteric coating layer: 30g acrylic resin L100-55, 2g sodium alginate, 0.75g CaCl2, 1.25g glycerin and 16g talc.

[0038] The preparation method includes the following steps:

[0039] (1) Weigh fluoxetine hydrochloride and hydroxypropyl methylcellulose succinate, add them to ethanol / water = 80 / 20 (v / v), stir for 30 min until clear, spray dry under the following conditions: feed temperature: 45℃, outlet air temperature: 95℃, feed rate: 5mL / min, to obtain a solid dispersion;

[0040] (2) Mix solid dispersion, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, lactose, and pregelatinized starch to prepare a 5% PVP-K30 aqueous solution. Spray the binder into the mixture while stirring, and continue stirring to form wet soft granules. Dry in a fluidized bed at 45°C for 15 minutes. Granulate the granules with a sieve aperture of 0.8 mm, add magnesium stearate, mix for 2 minutes, and compress the tablets using a rotary tablet press. The hardness is controlled at 120 N to obtain the tablet core.

[0041] (3) Ordinary film coating layer: Hydroxypropyl methylcellulose and succinic acid are dissolved in water and heated to 60°C. The spray gun temperature is 50°C. The liquid is sprayed.

[0042] (4) Enteric gel coating layer: a. Take water / ethanol (volume ratio 70:30) solvent, add acrylic resin L100-55 under stirring, stir until uniformly dispersed, add sodium alginate, continue stirring until uniformly dissolved / colloidal, add glycerol and stir evenly; b. Take water to dissolve CaCl2 to prepare a low concentration solution, slowly add it to the solution prepared in step a under stirring to avoid local gel lumps, add talc powder that has been pre-sieved through a 200-mesh sieve to form a uniform suspension system, filter once through an 80-mesh sieve, let stand to remove bubbles, and obtain the coating solution; c. Load the film cores coated with ordinary film layer into the coating pan; preheat to the film bed temperature of 38℃, spray, dynamically adjust the air volume, spray speed and angle during the spraying process to avoid film sticking and spray spots; after spraying, continue hot air drying for 15 minutes, and finally cool with cold air for 8 minutes; check that the enteric layer is intact, undamaged and without obvious spray spots.

[0043] Example 2:

[0044] Raw material preparation:

[0045] (1) Tablet core: 90g fluoxetine hydrochloride, 180g hydroxypropyl methylcellulose acetate succinate, 90g microcrystalline cellulose, 20g low-substituted hydroxypropyl cellulose, 30g lactose, 10g pregelatinized starch and 4g magnesium stearate.

[0046] (2) The ordinary film coating layer is prepared from the following raw materials in parts by weight: 10g of hydroxypropyl methylcellulose and 10g of succinic acid;

[0047] (3) The enteric coating layer is prepared from the following raw materials in parts by weight: acrylic resin L100-5520g, sodium alginate 3g, CaCl2 0.75g, glycerin 1.25g and talc 10g.

[0048] The preparation method includes the following steps:

[0049] (1) Weigh fluoxetine hydrochloride and hydroxypropyl methylcellulose succinate, add them to ethanol / water = 80 / 20 (v / v), stir for 30 min until clear, spray dry under the following conditions: feed temperature: 45℃, outlet air temperature: 95℃, feed rate: 5mL / min, to obtain a solid dispersion;

[0050] (2) Mix solid dispersion, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, lactose, and pregelatinized starch to prepare a 5% PVP-K30 aqueous solution. Spray the binder into the mixture while stirring, and continue stirring to form wet soft granules. Dry in a fluidized bed at 45°C for 15 minutes. Granulate the granules with a sieve aperture of 0.8 mm. Add magnesium stearate and mix for 2 minutes. Press the tablets with a rotary tablet press and control the hardness at 100 N to obtain the tablet core.

[0051] (3) Ordinary film coating layer: Hydroxypropyl methylcellulose and succinic acid are dissolved in water and heated to 60°C. The spray gun temperature is 50°C. The liquid is sprayed.

[0052] (4) Enteric gel coating layer: a. Take water / ethanol (volume ratio 70:30) solvent, add acrylic resin L100-55 under stirring, stir until uniformly dispersed, add sodium alginate, continue stirring until uniformly dissolved / colloidal, add glycerol and stir evenly; b. Take water to dissolve CaCl2 to prepare a low concentration solution, slowly add it to the solution prepared in step a under stirring to avoid local gel lumps, add talc powder that has been pre-sieved through a 200-mesh sieve to form a uniform suspension system, filter once through an 80-mesh sieve, let stand to remove bubbles, and obtain the coating solution; c. Load the film cores coated with ordinary film layer into the coating pan; preheat to the film bed temperature of 40℃, spray, dynamically adjust the air volume, spray speed and angle during the spraying process to avoid film sticking and spray spots; after spraying, continue hot air drying for 10 minutes, and finally cool with cold air for 10 minutes; check that the enteric layer is intact, undamaged and without obvious spray spots.

[0053] Example 3:

[0054] Raw material preparation:

[0055] (1) Tablet core: 90g fluoxetine hydrochloride, 360g hydroxypropyl methylcellulose succinate acetate, 50g microcrystalline cellulose, 40g low-substituted hydroxypropyl cellulose, 20g lactose, 20g pregelatinized starch and 2g magnesium stearate.

[0056] (2) Ordinary film coating layer: 30g hydroxypropyl methylcellulose, 5g succinic acid;

[0057] (3) Enteric coating layer: 40g acrylic resin L100-55, 1g sodium alginate, 0.75g CaCl2, 1.25g glycerin and 30g talc.

[0058] The preparation method includes the following steps:

[0059] (1) Weigh fluoxetine hydrochloride and hydroxypropyl methylcellulose succinate, add them to ethanol / water = 80 / 20 (v / v), stir for 30 min until clear, spray dry under the following conditions: feed temperature: 45℃, outlet air temperature: 95℃, feed rate: 5mL / min, to obtain a solid dispersion;

[0060] (2) Mix solid dispersion, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, lactose, and pregelatinized starch to prepare a 5% PVP-K30 aqueous solution. Spray the binder into the mixture while stirring, and continue stirring to form wet soft granules. Dry in a fluidized bed at 45°C for 15 minutes. Granulate the granules with a sieve aperture of 0.8 mm. Add magnesium stearate and mix for 2 minutes. Compress the granules using a rotary tablet press and control the hardness at 130 N to obtain tablet cores.

[0061] (3) Ordinary film coating layer: Hydroxypropyl methylcellulose and succinic acid are dissolved in water and heated to 60°C. The spray gun temperature is 50°C. The liquid is sprayed.

[0062] (4) Enteric gel coating layer: a. Take water / ethanol (volume ratio 70:30) solvent, add acrylic resin L100-55 under stirring, stir until uniformly dispersed, add sodium alginate, continue stirring until uniformly dissolved / colloidal, add glycerol and stir evenly; b. Take water to dissolve CaCl2 to prepare a low concentration solution, slowly add it to the solution prepared in step a under stirring to avoid local gel lumps, add talc powder that has been pre-sieved through a 200-mesh sieve to form a uniform suspension system, filter once through an 80-mesh sieve, let stand to remove bubbles, and obtain the coating solution; c. Load the film cores coated with ordinary film layer into the coating pan; preheat to the film bed temperature of 35℃, spray, dynamically adjust the air volume, spray speed and angle during the spraying process to avoid film sticking and spray spots; after spraying, continue hot air drying for 20 minutes, and finally cool with cold air for 5 minutes; check that the enteric layer is intact, undamaged and without obvious spray spots.

[0063] Comparative Example 1:

[0064] Raw material preparation:

[0065] (1) Tablet core: 90g fluoxetine hydrochloride, 340g microcrystalline cellulose, 28g low-substituted hydroxypropyl cellulose, 25g lactose, 15g pregelatinized starch and 3g magnesium stearate;

[0066] (2) Ordinary film coating layer: 17.5g hydroxypropyl methylcellulose, 7.5g succinic acid;

[0067] (3) Enteric coating layer: 30g acrylic resin L100-55, 2g sodium alginate, 0.75g CaCl2, 1.25g glycerin and 16g talc.

[0068] The preparation method includes the following steps:

[0069] (1) Weigh fluoxetine hydrochloride and add it to ethanol / water = 80 / 20 (v / v). Stir for 30 min until clear. Spray dry under the following conditions: feed temperature: 45℃, outlet air temperature: 95℃, feed rate: 5mL / min to obtain a solid dispersion.

[0070] (2) Mix solid dispersion, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, lactose, and pregelatinized starch to prepare a 5% PVP-K30 aqueous solution. Spray the binder into the mixture while stirring, and continue stirring to form wet soft granules. Dry in a fluidized bed at 45°C for 15 minutes. Granulate the granules with a sieve aperture of 0.8 mm, add magnesium stearate, mix for 2 minutes, and compress the tablets using a rotary tablet press. The hardness is controlled at 120 N to obtain the tablet core.

[0071] (3) Ordinary film coating layer: Hydroxypropyl methylcellulose and succinic acid are dissolved in water and heated to 60°C. The spray gun temperature is 50°C. The liquid is sprayed.

[0072] (4) Enteric gel coating layer: a. Take water / ethanol (volume ratio 70:30) solvent, add acrylic resin L100-55 under stirring, stir until uniformly dispersed, add sodium alginate, continue stirring until uniformly dissolved / colloidal, add glycerol and stir evenly; b. Take water to dissolve CaCl2 to prepare a low concentration solution, slowly add it to the solution prepared in step a under stirring to avoid local gel lumps, add talc powder that has been pre-sieved through a 200-mesh sieve to form a uniform suspension system, filter once through an 80-mesh sieve, let stand to remove bubbles, and obtain the coating solution; c. Load the film cores coated with ordinary film layer into the coating pan; preheat to the film bed temperature of 38℃, spray, dynamically adjust the air volume, spray speed and angle during the spraying process to avoid film sticking and spray spots; after spraying, continue hot air drying for 15 minutes, and finally cool with cold air for 8 minutes; check that the enteric layer is intact, undamaged and without obvious spray spots.

[0073] Comparative Example 2:

[0074] Raw material preparation:

[0075] (1) Tablet core: 90g fluoxetine hydrochloride, 340g hydroxypropyl methylcellulose acetate succinate, 28g low-substituted hydroxypropyl cellulose, 25g lactose, 15g pregelatinized starch and 3g magnesium stearate.

[0076] (2) Ordinary film coating layer: 17.5g hydroxypropyl methylcellulose, 7.5g succinic acid;

[0077] (3) Enteric coating layer: 30g acrylic resin L100-55, 2g sodium alginate, 0.75g CaCl2, 1.25g glycerin and 16g talc.

[0078] The preparation method includes the following steps:

[0079] (1) Weigh fluoxetine hydrochloride and hydroxypropyl methylcellulose succinate, add them to ethanol / water = 80 / 20 (v / v), stir for 30 min until clear, spray dry under the following conditions: feed temperature: 45℃, outlet air temperature: 95℃, feed rate: 5mL / min, to obtain a solid dispersion;

[0080] (2) Mix solid dispersion, low-substituted hydroxypropyl cellulose, lactose and pregelatinized starch to prepare 5% PVP-K30 aqueous solution. Spray the binder into the mixture while stirring and continue stirring to form wet soft granules. Dry in fluidized bed at 45℃ for 15 min. Granulate the granules with a sieve aperture of 0.8 mm, add magnesium stearate, mix for 2 min, and compress with a rotary tablet press. Control the hardness at 120 N to obtain tablet cores.

[0081] (3) Ordinary film coating layer: Hydroxypropyl methylcellulose and succinic acid are dissolved in water and heated to 60°C. The spray gun temperature is 50°C. The liquid is sprayed.

[0082] (4) Enteric gel coating layer: a. Take water / ethanol (volume ratio 70:30) solvent, add acrylic resin L100-55 under stirring, stir until uniformly dispersed, add sodium alginate, continue stirring until uniformly dissolved / colloidal, add glycerol and stir evenly; b. Take water to dissolve CaCl2 to prepare a low concentration solution, slowly add it to the solution prepared in step a under stirring to avoid local gel lumps, add talc powder that has been pre-sieved through a 200-mesh sieve to form a uniform suspension system, filter once through an 80-mesh sieve, let stand to remove bubbles, and obtain the coating solution; c. Load the film cores coated with ordinary film layer into the coating pan; preheat to the film bed temperature of 38℃, spray, dynamically adjust the air volume, spray speed and angle during the spraying process to avoid film sticking and spray spots; after spraying, continue hot air drying for 15 minutes, and finally cool with cold air for 8 minutes; check that the enteric layer is intact, undamaged and without obvious spray spots.

[0083] Comparative Example 3:

[0084] Raw material preparation:

[0085] (1) Tablet core: 90g fluoxetine hydrochloride, 270g hydroxypropyl methylcellulose succinate acetate, 70g microcrystalline cellulose, 28g low-substituted hydroxypropyl cellulose, 25g lactose, 15g pregelatinized starch and 3g magnesium stearate.

[0086] (2) Ordinary film coating layer: 17.5g of hydroxypropyl methylcellulose;

[0087] (3) Enteric coating layer: 30g acrylic resin L100-55, 2g sodium alginate, 0.75g CaCl2, 1.25g glycerin and 16g talc.

[0088] The preparation method includes the following steps:

[0089] (1) Weigh fluoxetine hydrochloride and hydroxypropyl methylcellulose succinate, add them to ethanol / water = 80 / 20 (v / v), stir for 30 min until clear, spray dry under the following conditions: feed temperature: 45℃, outlet air temperature: 95℃, feed rate: 5mL / min, to obtain a solid dispersion;

[0090] (2) Mix solid dispersion, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, lactose, and pregelatinized starch to prepare a 5% PVP-K30 aqueous solution. Spray the binder into the mixture while stirring, and continue stirring to form wet soft granules. Dry in a fluidized bed at 45°C for 15 minutes. Granulate the granules with a sieve aperture of 0.8 mm, add magnesium stearate, mix for 2 minutes, and compress the tablets using a rotary tablet press. The hardness is controlled at 120 N to obtain the tablet core.

[0091] (3) Ordinary film coating layer: Hydroxypropyl methylcellulose is dissolved in water and heated to 60°C. The spray gun temperature is 50°C. The liquid is sprayed.

[0092] (4) Enteric gel coating layer: a. Take water / ethanol (volume ratio 70:30) solvent, add acrylic resin L100-55 under stirring, stir until uniformly dispersed, add sodium alginate, continue stirring until uniformly dissolved / colloidal, add glycerol and stir evenly; b. Take water to dissolve CaCl2 to prepare a low concentration solution, slowly add it to the solution prepared in step a under stirring to avoid local gel lumps, add talc powder that has been pre-sieved through a 200-mesh sieve to form a uniform suspension system, filter once through an 80-mesh sieve, let stand to remove bubbles, and obtain the coating solution; c. Load the film cores coated with ordinary film layer into the coating pan; preheat to the film bed temperature of 38℃, spray, dynamically adjust the air volume, spray speed and angle during the spraying process to avoid film sticking and spray spots; after spraying, continue hot air drying for 15 minutes, and finally cool with cold air for 8 minutes; check that the enteric layer is intact, undamaged and without obvious spray spots.

[0093] Comparative Example 4:

[0094] Raw material preparation:

[0095] (1) Tablet core: 90g fluoxetine hydrochloride, 270g hydroxypropyl methylcellulose succinate acetate, 70g microcrystalline cellulose, 28g low-substituted hydroxypropyl cellulose, 25g lactose, 15g pregelatinized starch and 3g magnesium stearate.

[0096] (2) Ordinary film coating layer: 17.5g hydroxypropyl methylcellulose, 7.5g succinic acid;

[0097] (3) Enteric coating layer: acrylic resin L100-5530g, CaCl2 0.75g, glycerin 1.25g and talc 16g.

[0098] The preparation method includes the following steps:

[0099] (1) Weigh fluoxetine hydrochloride and hydroxypropyl methylcellulose succinate, add them to ethanol / water = 80 / 20 (v / v), stir for 30 min until clear, spray dry under the following conditions: feed temperature: 45℃, outlet air temperature: 95℃, feed rate: 5mL / min, to obtain a solid dispersion;

[0100] (2) Mix solid dispersion, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, lactose, and pregelatinized starch to prepare a 5% PVP-K30 aqueous solution. Spray the binder into the mixture while stirring, and continue stirring to form wet soft granules. Dry in a fluidized bed at 45°C for 15 minutes. Granulate the granules with a sieve aperture of 0.8 mm, add magnesium stearate, mix for 2 minutes, and compress the tablets using a rotary tablet press. The hardness is controlled at 120 N to obtain the tablet core.

[0101] (3) Ordinary film coating layer: Hydroxypropyl methylcellulose and succinic acid are dissolved in water and heated to 60°C. The spray gun temperature is 50°C. The liquid is sprayed.

[0102] (4) Enteric gel coating layer: a. Take water / ethanol (volume ratio 70:30) solvent, add acrylic resin L100-55 under stirring, stir until uniformly dispersed, add glycerol and stir evenly; b. Take water to dissolve CaCl2 to make a low concentration solution, slowly add it to the solution prepared in step a under stirring to avoid local gel lumps, add talc powder that has been passed through a 200-mesh sieve to form a uniform suspension system, filter once through an 80-mesh sieve, let stand to remove bubbles, and obtain the coating solution; c. Put the film cores with ordinary film coating into the coating pan; preheat to the film bed temperature of 38℃, spray, dynamically adjust the air volume, spray speed and angle during the spraying process to avoid film sticking and spray spots; after spraying, continue hot air drying for 15 minutes, and finally cool with cold air for 8 minutes; check that the enteric layer is intact, undamaged and without obvious spray spots.

[0103] Example 4:

[0104] The fluoxetine hydrochloride tablets prepared in Examples 1-3 and Comparative Examples 1-4 were subjected to in vitro dissolution tests in 750 ml of water at 37℃±0.5℃ and pH=1.2, according to the Chinese Pharmacopoeia 2020 edition and the 100 rpm leaf dissolution method. After 2 hours in acid, the release rates of the fluoxetine hydrochloride tablets in Examples 1-3 and Comparative Examples 1-3 did not exceed 5%. After 2 hours, 250 ml of Na3PO4 aqueous solution with pH=12.5 was added to obtain a buffer solution with pH=6.8. The release rates of the fluoxetine hydrochloride tablets in the buffer solution in Examples 1-3 and Comparative Examples 1-4 are shown in Table 1 and [Table 2 missing in original text].Figure 1 .

[0105] Table 1. Release rate of fluoxetine hydrochloride tablets in artificial intestinal fluid after 2 hours of acid treatment.

[0106]

[0107] According to Table 1 and Figure 1 The experimental results show that the fluoxetine hydrochloride tablets of Examples 1-3 of this invention have stable release. Comparative Example 1 did not use hydroxypropyl methylcellulose acetate succinate in the preparation of the fluoxetine hydrochloride tablets, and Comparative Example 2 did not use microcrystalline cellulose, resulting in insufficient sustained release. Comparative Example 3 did not use succinic acid, and Comparative Example 4 did not use sodium alginate, thus failing to achieve a sustained release effect; however, at 36 hours, 75% of the drug had been released. The experimental results indicate that a specific combination of fluoxetine hydrochloride and hydroxypropyl methylcellulose acetate succinate has a very significant impact on the sustained release of the drug. The best sustained release effect is achieved when the weight ratio of fluoxetine hydrochloride to hydroxypropyl methylcellulose acetate succinate is 1:3 and the weight ratio of fluoxetine hydrochloride to microcrystalline cellulose is 9:7.

[0108] Example 5: Long-term stability test of fluoxetine hydrochloride long-acting tablets

[0109] Samples from Examples 1-3 and Comparative Examples 1-4 were taken, and their packaging was simulated for commercial use. They were placed in a constant temperature and humidity chamber under long-term test conditions (temperature: 25℃±2℃, humidity: 60%±5%). Samples were taken for analysis at the 6th, 12th, 18th and 24th months of the test period. The test data are shown in Table 2.

[0110] Table 2 Comparison of long-term stability data of fluoxetine hydrochloride long-acting tablets

[0111]

[0112]

[0113] Table 2 shows that, compared with Comparative Examples 1-4, the long-acting fluoxetine hydrochloride tablets of the present invention remained stable in quality after 6 months of accelerated stability testing (conditions: 40℃±2℃ / relative humidity 75%±5%). The tablets were white in appearance, with total impurities not exceeding 0.2%, and the content remained essentially unchanged. Example 1 showed the best results. Comparative Example 1 did not use hydroxypropyl methylcellulose acetate succinate in the preparation of the fluoxetine hydrochloride tablets; Comparative Example 2 did not use microcrystalline cellulose, and therefore did not form a stable solid dispersion. Comparative Example 3 did not use succinic acid; Comparative Example 4 did not use sodium alginate, and therefore could not form a gel network with calcium chloride (CaCl2), thus failing to achieve the effect of delaying the degradation of fluoxetine hydrochloride.

[0114] This invention utilizes hydroxypropyl methylcellulose acetate succinate and fluoxetine hydrochloride to form an amorphous solid dispersion via spray drying. HPMCAS, as an amphiphilic polymer, not only significantly improves the apparent solubility of fluoxetine, but more importantly, it is insoluble in gastric acid (pH 1.2), effectively inhibiting supersaturated precipitation and burst release of the drug in the stomach. When the formulation enters the intestine (pH ≥ 5.5), HPMCAS dissolves, and the drug is continuously released in its molecular state, thus achieving a stable and long-lasting release from the stomach to the intestine. Simultaneously, freezing the drug molecules within the amorphous polymer network effectively inhibits recrystallization and chemical degradation, which is one of the fundamental reasons for the excellent long-term stability of this formulation.

[0115] The ordinary film coating layer is not a simple film coating, but a functional pH-responsive layer. Succinic acid has low solubility in acidic environments and forms a dense film with HPMC, providing additional protection for the tablet core. When it enters the intestinal fluid, succinic acid dissolves rapidly, not only forming microporous channels in the coating film, but more importantly, it locally lowers the pH value of the microenvironment, promoting the dissolution of the acrylic resin (L100-55) in the enteric coating layer and the swelling of the sodium alginate gel. This precisely initiates and regulates the drug release rate, avoiding the problem of slow or incomplete release in the intestines of conventional enteric formulations.

[0116] The enteric coating of this invention is a unique enteric-gel coupling system. Its mechanism of action is twofold: First, enteric protection. Acrylic resin L100-55 provides basic resistance to gastric acid, ensuring the tablet safely passes through the stomach. Second, ion-crosslinked gel controlled release. This is the core of this invention. After entering the intestines, the external calcium ions (Ca... 2+ The drug diffuses inward through channels formed by the dissolution of acrylic resin, undergoing ionic cross-linking with the guluronic acid (G units) of sodium alginate, thus forming a hydrated gel barrier in situ. The drug must pass through this continuously dissolving and diffusing gel layer to be released. By adjusting the ratio of sodium alginate to CaCl2, the gel density and dissolution rate can be precisely controlled, thereby achieving precise programming of the drug release cycle (up to 168 hours, or one week). This mechanism overcomes the shortcomings of sustained-release technologies that rely solely on polymer dissolution or diffusion.

[0117] In summary, this invention synergistically prepares fluoxetine hydrochloride tablets using solid dispersion technology in the tablet core, pH-responsive triggering technology in the isolation layer, and ion-crosslinked gel controlled-release technology in the enteric coating layer. This system is not a simple superposition of its components, but rather achieves the following through functional complementarity and temporal control: 1) near-zero release in the stomach with strict enteric coating; 2) continuous, stable drug release in the intestines for up to one week; and 3) significantly improved chemical stability of the formulation during storage. These combined effects ultimately achieve the invention's objective of reducing dosing frequency, improving medication safety, and enhancing patient compliance.

[0118] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A long-acting fluoxetine hydrochloride tablet, comprising a tablet core, a common film coating layer, and an enteric coating layer, characterized in that, Specifically: (1) The core of the tablet comprises a solid dispersion made of fluoxetine hydrochloride and hydroxypropyl methylcellulose acetate succinate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, lactose, pregelatinized starch and magnesium stearate. (2) The ordinary film coating layer contains hydroxypropyl methylcellulose and succinic acid; (3) The enteric coating layer is composed of enteric acrylic resin, sodium alginate, soluble calcium salt CaCl2, glycerol and talc.

2. The long-acting fluoxetine hydrochloride tablet according to claim 1, comprising a tablet core, a common film coating layer, and an enteric coating layer, characterized in that, Specifically: (1) The core of the tablet is prepared from the following raw materials in parts by weight: 9 parts of fluoxetine hydrochloride, 18-36 parts of hydroxypropyl methylcellulose acetate succinate, 5-9 parts of microcrystalline cellulose, 2-4 parts of low-substituted hydroxypropyl cellulose, 2-3 parts of lactose, 1-2 parts of pregelatinized starch and 0.2-0.4 parts of magnesium stearate; (2) The ordinary film coating layer is prepared from the following raw materials in parts by weight: 1-3 parts of hydroxypropyl methylcellulose and 0.5-1 parts of succinic acid; (3) The enteric coating layer is prepared from the following raw materials in parts by weight: 2-4 parts enteric acrylic resin, 0.1-0.3 parts sodium alginate, 0.075 parts soluble calcium salt, 0.125 parts glycerol and 1-3 parts talc.

3. The long-acting fluoxetine hydrochloride tablet according to claim 1, comprising a tablet core, a common film coating layer, and an enteric coating layer, characterized in that, Specifically: (1) The core of the tablet is prepared from the following raw materials in parts by weight: 9 parts of fluoxetine hydrochloride, 27 parts of hydroxypropyl methylcellulose acetate succinate, 7 parts of microcrystalline cellulose, 2.8 parts of low-substituted hydroxypropyl cellulose, 2.5 parts of lactose, 1.5 parts of pregelatinized starch and 0.3 parts of magnesium stearate; (2) The ordinary film coating layer is prepared from the following raw materials in parts by weight: 1.75 parts of hydroxypropyl methylcellulose and 0.75 parts of succinic acid; (3) The enteric coating layer is prepared from the following raw materials in parts by weight: 3 parts enteric acrylic resin, 0.2 parts sodium alginate, 0.075 parts soluble calcium salt, 0.125 parts glycerol and 1.6 parts talc.

4. The long-acting fluoxetine hydrochloride tablet according to claim 1, characterized in that: The preparation method includes the following steps: (1) Weigh fluoxetine hydrochloride and hydroxypropyl methylcellulose succinate, add them to ethanol / water = 80 / 20 (v / v), stir for 30 min until clear, spray dry under the following conditions: feed temperature: 45℃, outlet air temperature: 95℃, feed rate: 5mL / min, to obtain a solid dispersion; (2) Mix solid dispersion, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, lactose, and pregelatinized starch to prepare a 5% PVP-K30 aqueous solution. Spray the binder into the mixture while stirring, and continue stirring to form wet soft granules. Dry in a fluidized bed at 45°C for 15 minutes. Granulate the granules with a sieve aperture of 0.8 mm. Add magnesium stearate and mix for 2 minutes. Compress the granules using a rotary tablet press and control the hardness at 100-130 N to obtain tablet cores. (3) Ordinary film coating layer: Hydroxypropyl methylcellulose and succinic acid are dissolved in water and heated to 60°C. The spray gun temperature is 50°C. The liquid is sprayed. (4) Enteric gel coating layer: a. Take water / ethanol (volume ratio 70:30) solvent, add acrylic resin L100-55 under stirring, stir until uniformly dispersed, add sodium alginate, continue stirring until uniformly dissolved / colloidal, add glycerol and stir evenly; b. Take water to dissolve CaCl2 to prepare a low concentration solution, slowly add it to the solution prepared in step a under stirring to avoid local gel lumps, add talc powder that has been pre-sieved through a 200-mesh sieve to form a uniform suspension system, filter once through an 80-mesh sieve, let stand to remove bubbles, and obtain the coating solution; c. Load the film cores coated with ordinary film layer into the coating pan; preheat to the film bed temperature of 35-40℃, spray, dynamically adjust the air volume, spray speed and angle during the spraying process to avoid film sticking and spray spots; after spraying, continue hot air drying for 10-20 minutes, and finally cool with cold air for 5-10 minutes; check that the enteric layer is intact, undamaged and without obvious spray spots.

5. The long-acting fluoxetine hydrochloride tablet according to claim 1, comprising a tablet core, a common film coating layer, and an enteric coating layer, characterized in that: The weight gain of ordinary film coating is 3-8% of the core weight.

6. The long-acting fluoxetine hydrochloride tablet according to claim 1, comprising a tablet core, a common film coating layer, and an enteric coating layer, characterized in that: The weight gain of ordinary film coating is 4-6% of the core weight.

7. The long-acting fluoxetine hydrochloride tablet according to claim 1, comprising a tablet core, a common film coating layer, and an enteric coating layer, characterized in that: The weight gain of the enteric coating layer is 6-12% of the tablet core weight.

8. The long-acting fluoxetine hydrochloride tablet according to claim 1, comprising a tablet core, a common film coating layer, and an enteric coating layer, characterized in that: The weight gain of the enteric coating layer is 8-10% of the tablet core weight.

9. The long-acting fluoxetine hydrochloride tablet according to claim 1, comprising a tablet core, a common film coating layer, and an enteric coating layer, characterized in that: Less than 5% is released in acidic conditions within 2 hours; 40-70% is released cumulatively over 36-72 hours under pH 6.8 conditions.

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