Codeine phosphate and aspirin compound tablet and preparation method thereof

Abstract

According to the codeine phosphate and aspirin compound tablet and the preparation method thereof, aspirin acts on the periphery, codeine acts on the center, and the aspirin and the codeine are combined to enhance the analgesic effect through different mechanisms. According to the invention, a three-layer tabletting process is combined with an interface isolation technology, aspirin and codeine are isolated by using starch, a three-layer tablet is prepared, and the codeine phosphate layer and the aspirin layer are spatially isolated by the three-layer tablet structure, so that the chemical stability of codeine phosphate and aspirin is ensured; meanwhile, the characteristics of each layer are optimized through layering treatment, and the dissolution rate of main components is improved.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to a codeine phosphate and aspirin compound tablet and a preparation method thereof. Background Art

[0002] Codeine phosphate is a centrally acting antitussive that selectively inhibits the cough center in the medulla oblongata. Its antitussive effect is strong and rapid, and it also has analgesic properties, with an intensity of approximately 1 / 12 to 1 / 7 that of morphine, but stronger than general antipyretic analgesics. Codeine phosphate is readily absorbed from the gastrointestinal tract after oral administration, primarily distributed in the lungs, liver, kidneys, and pancreas. It readily crosses the blood-brain barrier and the placenta. Codeine phosphate tablets are a product with clear clinical value and no reference preparation. Aspirin is primarily used as an antipyretic, analgesic, nonsteroidal anti-inflammatory drug, and antiplatelet agent. It is effective in relieving mild to moderate pain, such as toothache, headache, neuralgia, muscle aches, and dysmenorrhea. It is also used to reduce fever in febrile illnesses such as colds and influenza, and to treat rheumatic pain. Aspirin acts peripherally, while codeine acts centrally. The combination of the two enhances analgesic efficacy through different mechanisms. However, a mature process for preparing codeine phosphate-aspirin combination tablets is currently lacking.

[0003] Chinese patent CN108078988A discloses a diclofenac sodium and codeine phosphate compound sustained-release composition and its preparation method. The composition comprises first preparing diclofenac sodium granules and codeine phosphate sesquihydrate granules separately, then mixing the two granules and punching them into tablets or capsules. However, during storage, direct contact between diclofenac sodium and codeine phosphate sesquihydrate can lead to degradation of diclofenac sodium and oxidation of codeine phosphate sesquihydrate, affecting the quality and efficacy of the composition. Summary of the Invention

[0004] In order to overcome the above-mentioned deficiencies in the prior art, the present invention provides a codeine phosphate and aspirin compound tablet and a preparation method thereof through crystal engineering, process innovation and coordination of excipients.

[0005] The purpose of the present invention is achieved by at least one of the following technical solutions.

[0006] A codeine phosphate and aspirin compound tablet comprises a codeine phosphate layer, a starch layer and an aspirin layer, wherein the starch layer spatially isolates the codeine phosphate layer from the aspirin layer.

[0007] Furthermore, the mass ratio of the codeine phosphate layer, the starch layer and the aspirin layer is 147.01-149.77:40:578.656-600.368.

[0008] The raw materials of the aspirin layer are calculated in parts by weight and include:

[0009] 400 aspirin tablets

[0010]

[0011] The disintegrant 1 includes low-substituted hydroxypropyl cellulose;

[0012] The raw materials of the codeine phosphate layer are calculated in parts by weight and include:

[0013]

[0014] The disintegrant 2 includes low-substituted hydroxypropyl cellulose;

[0015] Furthermore, the adhesive comprises 8% starch slurry.

[0016] Furthermore, the codeine phosphate includes codeine phosphate hemihydrate and / or codeine phosphate sesquihydrate.

[0017] Furthermore, the codeine phosphate is codeine phosphate hemihydrate.

[0018] The method for preparing a codeine phosphate and aspirin compound tablet described in any one of the above items comprises the following steps:

[0019] (1) granulating aspirin and tableting to obtain an aspirin tablet;

[0020] (2) adding starch to the aspirin sheet layer and pressing the sheet to obtain an aspirin sheet layer-starch layer;

[0021] (3) Granulating the codeine phosphate, placing the codeine phosphate granules on the aspirin sheet layer-starch layer, and tableting, wherein the tablet hardness after tableting is 40-70N, to obtain a codeine phosphate and aspirin compound tablet.

[0022] Furthermore, the aspirin granulation method comprises the following steps:

[0023] A1: Mix aspirin, starch, and citric acid evenly;

[0024] A2: Add the binder at a uniform speed to granulate to obtain aspirin wet granules;

[0025] A3: Dry the wet aspirin granules to a moisture content of ≤3%, sieve, and granulate;

[0026] A4: Add talc and disintegrant 2 to obtain aspirin granules;

[0027] The granulation method of codeine phosphate comprises the following steps:

[0028] B1: using an equal amount incremental mixing method, codeine phosphate and beta-cyclodextrin are uniformly mixed to obtain codeine phosphate mixed particles;

[0029] B2: Add disintegrant 1 and talc to the codeine phosphate mixed granules, mix well, and obtain codeine phosphate granules.

[0030] Furthermore, in step A2, the stirring speed of the wet granulation is 200-400 rpm; the shearing speed is 800-1200 rpm; and the granulation time is 1-2 min.

[0031] Furthermore, in step A2, the stirring speed of the wet granulation is 300 rpm; the shearing speed is 1000 rpm; and the granulation time is 1 min.

[0032] Furthermore, in step A3, the drying temperature is 50-60°C.

[0033] Furthermore, in step A3, during the drying process, the wet granules are turned over every 2 hours.

[0034] Furthermore, in step A4, the sieving is through a 20-mesh sieve.

[0035] Furthermore, the codeine phosphate and aspirin compound tablet comprises a codeine phosphate layer, a starch layer and an aspirin layer, and the starch layer spatially isolates the codeine phosphate layer from the aspirin layer.

[0036] Furthermore, the raw materials of the codeine phosphate layer include, by weight:

[0037]

[0038] The disintegrant 2 includes low-substituted hydroxypropyl cellulose;

[0039] The raw materials of the aspirin layer are calculated in parts by weight and include:

[0040]

[0041] The disintegrant 1 includes low-substituted hydroxypropyl cellulose.

[0042] More preferably, the adhesive comprises 8% starch slurry.

[0043] Furthermore, the codeine phosphate includes codeine phosphate hemihydrate and / or codeine phosphate sesquihydrate.

[0044] More preferably, the codeine phosphate is codeine phosphate hemihydrate.

[0045] Furthermore, the mass ratio of the codeine phosphate layer, the starch layer and the aspirin layer is 147.01-149.77:40:578.656-600.368.

[0046] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0047] (1) The present invention utilizes a three-layer tableting process combined with interfacial isolation technology, using starch to separate aspirin and codeine phosphate to form a three-layer tablet. The aspirin layer is produced using a high-shear wet granulation method; the codeine phosphate layer is produced using a physical mixing method, achieving spatial isolation between aspirin and codeine phosphate, thereby delaying drug degradation.

[0048] (2) The technology used ensures the chemical stability of codeine phosphate and aspirin, optimizes the characteristics of each layer through layered processing, improves the dissolution rate of the main components, and the resulting compound tablets have lower variability in content and dissolution rate, and have strong process controllability.

[0049] (3) Codeine phosphate sesquihydrate (containing 1.5 molecules of water of crystallization) is susceptible to crystal transformation during storage due to changes in ambient humidity, leading to crystal precipitation and deterioration of tablet performance. In a preferred embodiment of the present invention, crystal form optimization is used to reduce the risk of crystal precipitation, thereby avoiding changes in tablet hardness and fluctuations in dissolution. DETAILED DESCRIPTION

[0050] The specific implementation of the present invention is further described below with reference to the accompanying drawings and examples, but the implementation and protection of the present invention are not limited thereto. It should be noted that if there are any processes not particularly described in detail below, they can be implemented or understood by those skilled in the art with reference to the prior art. If the manufacturer of the reagents or instruments used is not indicated, they are deemed to be conventional products that can be purchased commercially.

[0051] In the present invention, the term "codeine phosphate sesquihydrate" or "codeine phosphate" refers to a compound having the following structural formula:

[0052]

[0053] In the present invention, the term "codeine phosphate hemihydrate" refers to a compound having the following structural formula:

[0054]

[0055] The sources of some raw materials in the examples of the present invention are as follows:

[0056] Codeine phosphate sesquihydrate: Manufacturer: Qinghai Pharmaceutical Co., Ltd.; Batch number: H20230801.

[0057] Codeine phosphate hemihydrate: Manufacturer: Qinghai Pharmaceutical Co., Ltd.; Batch number: QH-2002-1-LXR250224-1-S13.

[0058] Aspirin: Manufacturer: Huayin Qianchengsijin Pharmaceutical Co., Ltd.; Batch number: CLA2307022.

[0059] A first aspect of the present invention provides a codeine phosphate and aspirin compound tablet comprising a codeine phosphate layer, a starch layer and an aspirin layer, wherein the starch layer spatially isolates the codeine phosphate layer from the aspirin layer.

[0060] In some embodiments of the present invention, the raw materials of the codeine phosphate layer include, in parts by weight:

[0061]

[0062] The disintegrant 2 includes low-substituted hydroxypropyl cellulose;

[0063] The raw materials of the aspirin layer are calculated in parts by weight and include:

[0064]

[0065] The disintegrant 1 includes low-substituted hydroxypropyl cellulose.

[0066] Preferably, the adhesive comprises 8% starch slurry.

[0067] In some embodiments of the present invention, the codeine phosphate comprises codeine phosphate hemihydrate and / or codeine phosphate sesquihydrate. Preferably, the codeine phosphate is codeine phosphate hemihydrate.

[0068] In some embodiments of the present invention, the mass ratio of the codeine phosphate layer, the starch layer, and the aspirin layer is 147.01-149.77:40:578.656-600.368.

[0069] A second aspect of the present invention provides a method for preparing a codeine phosphate and aspirin compound tablet as described in any one of the above, comprising the following steps:

[0070] (1) granulating aspirin and tableting to obtain an aspirin tablet;

[0071] (2) adding starch to the aspirin sheet layer and pressing the sheet to obtain an aspirin sheet layer-starch layer;

[0072] (3) Granulating the codeine phosphate, placing the codeine phosphate granules on the aspirin sheet layer-starch layer, and tableting, wherein the tablet hardness after tableting is 40-70N, to obtain a codeine phosphate and aspirin compound tablet.

[0073] In some embodiments of the present invention, the aspirin granulation method comprises the following steps:

[0074] A1: Mix aspirin, starch, and citric acid evenly;

[0075] A2: Add the binder at a uniform speed to granulate to obtain aspirin wet granules;

[0076] A3: Dry the wet aspirin granules to a moisture content of ≤3%, sieve, and granulate;

[0077] A4: Add talc and disintegrant 2 to obtain aspirin granules;

[0078] The granulation method of codeine phosphate comprises the following steps:

[0079] B1: using an equal amount incremental mixing method, codeine phosphate and beta-cyclodextrin are uniformly mixed to obtain codeine phosphate mixed particles;

[0080] B2: Add disintegrant 1 and talc to the codeine phosphate mixed granules, mix well, and obtain codeine phosphate granules.

[0081] In some embodiments of the present invention, in step A2, the stirring speed of the wet granulation is 200-400 rpm; the shearing speed is 800-1200 rpm; and the granulation time is 1-2 min. Preferably, in step A2, the stirring speed of the granulation is 300 rpm; the shearing speed is 1000 rpm; and the granulation time is 1-2 min. The prepared compound tablets have lower variability in content and dissolution rate and stronger process controllability.

[0082] In some embodiments of the present invention, in step A3, the drying temperature is 50-60°C.

[0083] In some embodiments of the present invention, in step A3, the wet granules are turned over every 2 hours during the drying process.

[0084] In some embodiments of the present invention, in step A4, the sieving is through a 20-mesh sieve.

[0085] In some embodiments of the present invention, the codeine phosphate and aspirin compound tablet comprises a codeine phosphate layer, a starch layer, and an aspirin layer, wherein the starch layer spatially isolates the codeine phosphate layer from the aspirin layer. Preferably, the raw materials of the codeine phosphate layer, in parts by weight, include:

[0086]

[0087] The disintegrant 2 includes low-substituted hydroxypropyl cellulose;

[0088] The raw materials of the aspirin layer are calculated in parts by weight and include:

[0089]

[0090] The disintegrant 1 includes low-substituted hydroxypropyl cellulose.

[0091] In one embodiment of the present invention, the adhesive comprises 8% starch slurry.

[0092] Preferably, the codeine phosphate comprises codeine phosphate hemihydrate and / or codeine phosphate sesquihydrate. In a specific embodiment of the present invention, the codeine phosphate is codeine phosphate hemihydrate.

[0093] Preferably, the mass ratio of the codeine phosphate layer, the starch layer and the aspirin layer is 147.01-149.77:40:578.656-600.368.

[0094] Example 1

[0095] Aspirin granules preparation:

[0096] A1: Premixing: Add aspirin, starch, and citric acid into a high shear wet granulator and stir until evenly mixed.

[0097] A2: Wet granulation: 8% starch slurry was added at a constant speed and the stirring blade and cutter were turned on to granulate to obtain wet granules (stirring speed: 300 rpm, shear speed: 1000 rpm, granulation time: 1 min);

[0098] A3: Drying: Transfer the wet granules to an oven and dry them at 55±5°C. Turn the oven over every 2 hours. Use a rapid moisture meter to control the moisture content to below 3% to obtain dry granules.

[0099] A4: Granulation: Pass the dried granules through a 20-mesh sieve;

[0100] A5: Mixing: After granulation, add the prescribed amount of talc and low-substituted hydroxypropyl cellulose to obtain aspirin granules.

[0101] Codeine phosphate granules preparation:

[0102] B1: Equal-amount incremental mixing: Using the equal-amount incremental mixing method, weigh the prescribed amount of codeine phosphate hemihydrate, add an equal amount of beta-cyclodextrin, and mix evenly to obtain a mixture. Then, add an equal amount of beta-cyclodextrin to the mixture and mix evenly. Repeat this process until the prescribed amount of beta-cyclodextrin is added to obtain codeine phosphate mixed granules.

[0103] B2: Disintegrant mixing: Add the prescribed amount of low-substituted hydroxypropyl cellulose and talc to the codeine phosphate mixed granules and mix well to obtain codeine phosphate granules;

[0104] Tablet pressing:

[0105] (1) First, the prescribed amount of aspirin granules is placed into a tablet press to form aspirin tablets (slightly loose);

[0106] (2) Spread the prescribed amount of starch evenly until the aspirin tablet completely covers the surface, and press the tablet again (slightly loose);

[0107] (3) Add codeine phosphate granules to the starch layer, adjust the tablet press to a tablet hardness of 40 to 70 N after tableting, and punch a 14 mm die to obtain codeine phosphate and aspirin compound tablets.

[0108] Example 1 The raw materials and composition of codeine phosphate and aspirin compound tablets are shown in Table 1.

[0109] Table 1 Example 1 Codeine phosphate and aspirin compound tablet raw materials and composition

[0110]

[0111] Codeine phosphate granules can be prepared in batches. The preparation method for a batch of 500 tablets is as follows: 4.2 g of codeine phosphate is added to 4.2 g of beta-cyclodextrin and mixed evenly, 8.4 g of beta-cyclodextrin is added again and mixed evenly, 16.8 g of beta-cyclodextrin is added and mixed evenly, 35.1 g of beta-cyclodextrin is added and mixed evenly, and finally the prescribed amount of low-substituted hydroxypropyl cellulose and talc are added.

[0112] Example 2

[0113] Aspirin granules preparation:

[0114] A1: Premixing: Add aspirin, starch, and citric acid into a high shear wet granulator and stir until evenly mixed.

[0115] A2: Wet granulation: 8% starch slurry was added at a constant speed and the stirring blade and cutter were turned on to granulate to obtain wet granules (stirring speed: 300 rpm, shear speed: 1000 rpm, granulation time: 1 min);

[0116] A3: Drying: Transfer the wet granules to an oven and dry them at 55±5°C. Turn the oven over every 2 hours. Use a rapid moisture meter to control the moisture content to below 3% to obtain dry granules.

[0117] A4: Granulation: Pass the dried granules through a 20-mesh sieve;

[0118] A5: Mixing: After granulation, add the prescribed amount of talc and low-substituted hydroxypropyl cellulose to obtain aspirin granules.

[0119] Codeine phosphate granules preparation:

[0120] B1: Equal-amount incremental mixing: Using the equal-amount incremental mixing method, weigh the prescribed amount of codeine phosphate hemihydrate, add an equal amount of beta-cyclodextrin, and mix evenly to obtain a mixture. Then, add an equal amount of beta-cyclodextrin to the mixture and mix evenly. Repeat this process until the prescribed amount of beta-cyclodextrin is added to obtain codeine phosphate mixed granules.

[0121] B2: Disintegrant mixing: Add the prescribed amount of low-substituted hydroxypropyl cellulose and talc to the codeine phosphate mixed granules and mix well to obtain codeine phosphate granules;

[0122] Tablet pressing:

[0123] (1) First, the prescribed amount of aspirin granules is placed into a tablet press to form aspirin tablets (slightly loose);

[0124] (2) Spread the prescribed amount of starch evenly until the aspirin tablet completely covers the surface, and press the tablet again (slightly loose);

[0125] (3) Add codeine phosphate granules to the starch layer, adjust the tablet press to a tablet hardness of 40 to 70 N after tableting, and punch a 14 mm die to obtain codeine phosphate and aspirin compound tablets.

[0126] Example 2 The raw materials and composition of codeine phosphate and aspirin compound tablets are shown in Table 2.

[0127] Table 2 Example 2 Codeine phosphate and aspirin compound tablet raw materials and composition

[0128]

[0129] Example 3

[0130] Aspirin granules preparation:

[0131] A1: Premixing: Add aspirin, starch, and citric acid into a high shear wet granulator and stir until evenly mixed.

[0132] A2: Wet granulation: 8% starch slurry was added at a constant speed and the stirring blade and cutter were turned on to granulate to obtain wet granules (stirring speed: 300 rpm, shear speed: 1000 rpm, granulation time: 1 min);

[0133] A3: Drying: Transfer the wet granules to an oven and dry them at 55±5°C. Turn the oven over every 2 hours. Use a rapid moisture meter to control the moisture content to below 3% to obtain dry granules.

[0134] A4: Granulation: Pass the dried granules through a 20-mesh sieve;

[0135] A5: Mixing: After granulation, add the prescribed amount of talc and low-substituted hydroxypropyl cellulose to obtain aspirin granules.

[0136] Codeine phosphate granules preparation:

[0137] B1: Equal-amount incremental mixing: Using the equal-amount incremental mixing method, weigh the prescribed amount of codeine phosphate hemihydrate, add an equal amount of beta-cyclodextrin, and mix evenly to obtain a mixture. Then, add an equal amount of beta-cyclodextrin to the mixture and mix evenly. Repeat this process until the prescribed amount of beta-cyclodextrin is added to obtain codeine phosphate mixed granules.

[0138] B2: Disintegrant mixing: Add the prescribed amount of low-substituted hydroxypropyl cellulose and talc to the codeine phosphate mixed granules and mix well to obtain codeine phosphate granules;

[0139] Tablet pressing:

[0140] (1) First, the prescribed amount of aspirin granules is placed into a tablet press to form aspirin tablets (slightly loose);

[0141] (2) Spread the prescribed amount of starch evenly until the aspirin tablet completely covers the surface, and press the tablet again (slightly loose);

[0142] (3) Add codeine phosphate granules to the starch layer, adjust the tablet press to a tablet hardness of 40 to 70 N after tableting, and punch a 14 mm die to obtain codeine phosphate and aspirin compound tablets.

[0143] Example 3 The raw materials and composition of codeine phosphate and aspirin compound tablets are shown in Table 3.

[0144] Table 3 Example 3 Codeine phosphate and aspirin compound tablet raw materials and composition

[0145]

[0146] Example 4

[0147] Aspirin granules preparation:

[0148] A1: Premixing: Add aspirin, starch, and citric acid into a high shear wet granulator and stir until evenly mixed.

[0149] A2: Wet granulation: 8% starch slurry was added at a constant speed and the stirring blade and cutter were turned on to granulate to obtain wet granules (stirring speed: 300 rpm, shear speed: 1000 rpm, granulation time: 1 min);

[0150] A3: Drying: Transfer the wet granules to an oven and dry them at 55±5°C. Turn the oven over every 2 hours. Use a rapid moisture meter to control the moisture content to below 3% to obtain dry granules.

[0151] A4: Granulation: Pass the dried granules through a 20-mesh sieve;

[0152] A5: Mixing: After granulation, add the prescribed amount of talc and low-substituted hydroxypropyl cellulose to obtain aspirin granules.

[0153] Codeine phosphate granules preparation:

[0154] B1: Equal-amount incremental mixing: Using the equal-amount incremental mixing method, weigh the prescribed amount of codeine phosphate hemihydrate, add an equal amount of beta-cyclodextrin, and mix evenly to obtain a mixture. Then, add an equal amount of beta-cyclodextrin to the mixture and mix evenly. Repeat this process until the prescribed amount of beta-cyclodextrin is added to obtain codeine phosphate mixed granules.

[0155] B2: Disintegrant mixing: Add the prescribed amount of low-substituted hydroxypropyl cellulose and talc to the codeine phosphate mixed granules and mix well to obtain codeine phosphate granules;

[0156] Tablet pressing:

[0157] (1) First, the prescribed amount of aspirin granules is placed into a tablet press to form aspirin tablets (slightly loose);

[0158] (2) Spread the prescribed amount of starch evenly until the aspirin tablet completely covers the surface, and press the tablet again (slightly loose);

[0159] (3) Add codeine phosphate granules to the starch layer, adjust the tablet press to a tablet hardness of 40 to 70 N after tableting, and punch a 14 mm die to obtain codeine phosphate and aspirin compound tablets.

[0160] Example 4 The raw materials and composition of codeine phosphate and aspirin compound tablets are shown in Table 4.

[0161] Table 4 Example 4 Codeine phosphate and aspirin compound tablet raw materials and composition

[0162]

[0163] Example 5

[0164] Aspirin granules preparation:

[0165] A1: Premixing: Add aspirin, starch, and citric acid into a high shear wet granulator and stir until evenly mixed.

[0166] A2: Wet granulation: 8% starch slurry was added at a constant speed and the stirring blade and cutter were turned on to granulate to obtain wet granules (stirring speed: 300 rpm, shear speed: 1000 rpm, granulation time: 1 min);

[0167] A3: Drying: Transfer the wet granules to an oven and dry them at 55±5°C. Turn the oven over every 2 hours. Use a rapid moisture meter to control the moisture content to below 3% to obtain dry granules.

[0168] A4: Granulation: Pass the dried granules through a 20-mesh sieve;

[0169] A5: Mixing: After granulation, add the prescribed amount of talc and low-substituted hydroxypropyl cellulose to obtain aspirin granules.

[0170] Codeine phosphate granules preparation:

[0171] B1: Equal-amount incremental mixing: Using the equal-amount incremental mixing method, weigh the prescribed amount of codeine phosphate hemihydrate, add an equal amount of beta-cyclodextrin, and mix evenly to obtain a mixture. Then, add an equal amount of beta-cyclodextrin to the mixture and mix evenly. Repeat this process until the prescribed amount of beta-cyclodextrin is added to obtain codeine phosphate mixed granules.

[0172] B2: Disintegrant mixing: Add the prescribed amount of low-substituted hydroxypropyl cellulose and talc to the codeine phosphate mixed granules and mix well to obtain codeine phosphate granules;

[0173] Tablet pressing:

[0174] (1) First, the prescribed amount of aspirin granules is placed into a tablet press to form aspirin tablets (slightly loose);

[0175] (2) Spread the prescribed amount of starch evenly until the aspirin tablet completely covers the surface, and press the tablet again (slightly loose);

[0176] (3) Add codeine phosphate granules to the starch layer, adjust the tablet press to a tablet hardness of 40 to 70 N after tableting, and punch a 14 mm die to obtain codeine phosphate and aspirin compound tablets.

[0177] Example 5 The raw materials and composition of codeine phosphate and aspirin compound tablets are shown in Table 5.

[0178] Table 5 Example 5 Codeine phosphate and aspirin compound tablet raw materials and composition

[0179]

[0180] Example 6

[0181] Aspirin granules preparation:

[0182] A1: Premixing: Add aspirin, starch, and citric acid into a high shear wet granulator and stir until evenly mixed.

[0183] A2: Wet granulation: 8% starch slurry was added at a constant speed and the stirring blade and cutter were turned on to granulate to obtain wet granules (stirring speed: 300 rpm, shear speed: 1000 rpm, granulation time: 1 min);

[0184] A3: Drying: Transfer the wet granules to an oven and dry them at 55±5°C. Turn the oven over every 2 hours. Use a rapid moisture meter to control the moisture content to below 3% to obtain dry granules.

[0185] A4: Granulation: Pass the dried granules through a 20-mesh sieve;

[0186] A5: Mixing: After granulation, add the prescribed amount of talc and low-substituted hydroxypropyl cellulose to obtain aspirin granules.

[0187] Codeine phosphate granules preparation:

[0188] B1: Equal amount incremental mixing: Using the equal amount incremental mixing method, weigh the prescribed amount of codeine phosphate sesquihydrate, add an equal amount of beta-cyclodextrin, and mix evenly to obtain a mixture. Then, add an equal amount of beta-cyclodextrin to the mixture and mix evenly. Repeat this process until the prescribed amount of beta-cyclodextrin is added to obtain codeine phosphate mixed particles.

[0189] B2: Disintegrant mixing: Add the prescribed amount of low-substituted hydroxypropyl cellulose and talc to the codeine phosphate mixed granules and mix well to obtain codeine phosphate granules;

[0190] Tablet pressing:

[0191] (1) First, the prescribed amount of aspirin granules is placed into a tablet press to form aspirin tablets (slightly loose);

[0192] (2) Spread the prescribed amount of starch evenly until the aspirin tablet completely covers the surface, and press the tablet again (slightly loose);

[0193] (3) Add codeine phosphate granules to the starch layer, adjust the tablet press to a tablet hardness of 40 to 70 N after tableting, and punch a 14 mm die to obtain codeine phosphate and aspirin compound tablets.

[0194] Example 6 The raw materials and composition of codeine phosphate and aspirin compound tablets are shown in Table 6.

[0195] Table 6 Example 6 Codeine phosphate and aspirin compound tablet raw materials and composition

[0196]

[0197] Comparative Example 1

[0198] Aspirin granule preparation process:

[0199] (1) Premixing: Add aspirin, starch, and citric acid into a high shear wet granulator and stir until uniformly mixed;

[0200] (2) Wet granulation: Add starch slurry at a uniform speed and turn on the stirring paddle and cutter to granulate (stirring speed: 300 rpm, shear speed: 1500 rpm, granulation time: 1 min);

[0201] (3) Drying: Transfer the wet granules to an oven and dry them at 55 ± 5 °C; turn the granules over every 2 hours; use a rapid moisture meter to control the moisture content to below 3%;

[0202] (4) Granulation: The aspirin granules are sieved through a 20-mesh sieve.

[0203] Preparation process of codeine phosphate inclusion complex:

[0204] Beta-cyclodextrin, codeine phosphate and purified water are added in sequence, mixed and stirred evenly, and then ground for 3 hours, heated at 70°C and dried until nearly dry, sieved with a Φ2.0mm or Φ2.5mm sieve plate, heated at 70°C, dried, and sieved through a 20-mesh sieve to obtain a codeine phosphate inclusion complex.

[0205] Mixing and tableting process:

[0206] Calculate the amount of low-substituted hydroxypropyl cellulose (LSHC) by (mass of aspirin granules + mass of codeine phosphate inclusion complex) x 6%; calculate the amount of talc by (mass of aspirin granules + mass of codeine phosphate inclusion complex) x 1%. Weigh the materials into a ziplock bag and manually mix 200 times. Compress the granules into tablets with a hardness of 40-70N using a 14mm die.

[0207] Comparative Example 1 The raw materials and composition of codeine phosphate and aspirin tablets are shown in Table 7.

[0208] Table 7 Comparative Example 1 Codeine phosphate and aspirin tablet raw materials and composition

[0209]

[0210] Comparative Example 2

[0211] Comparative Example 2 The raw materials and composition of codeine phosphate and aspirin tablets are shown in Table 8.

[0212] Aspirin granule preparation process:

[0213] (1) Premixing: Add aspirin, starch, and citric acid into a high shear wet granulator and stir until uniformly mixed;

[0214] (2) Wet granulation: Add starch slurry at a uniform speed and turn on the stirring paddle and cutter to granulate (stirring speed: 300 rpm, shear speed: 1500 rpm, granulation time: 1 min);

[0215] (3) Drying: Transfer the wet granules to an oven and dry them at 55 ± 5 °C; turn the granules over every 2 hours; use a rapid moisture meter to control the moisture content to below 3%;

[0216] (4) Granulation: The aspirin granules are sieved through a 20-mesh sieve.

[0217] Preparation process of codeine phosphate inclusion complex:

[0218] Beta-cyclodextrin, codeine phosphate and purified water are added in sequence, mixed and stirred evenly, and then ground for 3 hours, heated at 70°C and dried until nearly dry, sieved with a Φ2.0mm or Φ2.5mm sieve plate, heated at 70°C, dried, and sieved through a 20-mesh sieve to obtain a codeine phosphate inclusion complex.

[0219] Mixing and tableting process:

[0220] Calculate the amount of low-substituted hydroxypropyl cellulose (LSHC) by (mass of aspirin granules + mass of codeine phosphate inclusion complex) x 6%; calculate the amount of talc by (mass of aspirin granules + mass of codeine phosphate inclusion complex) x 1%. Weigh the materials into a ziplock bag and manually mix 200 times. Compress the granules into tablets with a hardness of 40-70N using a 14mm die.

[0221] Table 8 Comparative Example 2 Codeine Phosphate and Aspirin Tablet Raw Materials and Composition

[0222]

[0223] Comparative Example 3

[0224] Aspirin granules preparation:

[0225] A1: Premixing: Add aspirin, starch, and citric acid into a high shear wet granulator and stir until evenly mixed.

[0226] A2: Wet granulation: 8% starch slurry was added at a constant speed and the stirring blade and cutter were turned on to granulate to obtain wet granules (stirring speed: 300 rpm, shear speed: 1000 rpm, granulation time: 1 min);

[0227] A3: Drying: Transfer the wet granules to an oven and dry them at 55±5°C. Turn the oven over every 2 hours. Use a rapid moisture meter to control the moisture content to below 3% to obtain dry granules.

[0228] A4: Granulation: Pass the dried granules through a 20-mesh sieve;

[0229] A5: Mixing: After granulation, add the prescribed amount of talc and low-substituted hydroxypropyl cellulose to obtain aspirin granules.

[0230] Codeine phosphate granules preparation:

[0231] B1: Equal-amount incremental mixing: Using the equal-amount incremental mixing method, weigh the prescribed amount of codeine phosphate hemihydrate, add an equal amount of beta-cyclodextrin, and mix evenly to obtain a mixture. Then, add an equal amount of beta-cyclodextrin to the mixture and mix evenly. Repeat this process until the prescribed amount of beta-cyclodextrin is added to obtain codeine phosphate mixed granules.

[0232] B2: Disintegrant mixing: Add the prescribed amount of low-substituted hydroxypropyl cellulose and talc to the codeine phosphate mixed granules and mix well to obtain codeine phosphate granules;

[0233] Tablet pressing:

[0234] (1) First, the prescribed amount of aspirin granules is placed into a tablet press to form aspirin tablets (slightly loose);

[0235] (2) Spread the prescribed amount of starch evenly until the aspirin tablet completely covers the surface, and press the tablet again (slightly loose);

[0236] (3) Add codeine phosphate granules to the starch layer, adjust the tablet press to a tablet hardness of 40 to 70 N after tableting, and punch a 14 mm die to obtain codeine phosphate and aspirin compound tablets.

[0237] Comparative Example 3 The raw materials and composition of codeine phosphate and aspirin compound tablets are shown in Table 9.

[0238] Table 9 Comparative Example 3 Codeine Phosphate and Aspirin Compound Tablet Raw Materials and Composition

[0239]

[0240] Comparative Example 4

[0241] Aspirin granules preparation:

[0242] A1: Premixing: Add aspirin, starch, and citric acid into a high shear wet granulator and stir until evenly mixed.

[0243] A2: Wet granulation: 8% starch slurry was added at a constant speed and the stirring blade and cutter were turned on to granulate to obtain wet granules (stirring speed: 300 rpm, shear speed: 1000 rpm, granulation time: 1 min);

[0244] A3: Drying: Transfer the wet granules to an oven and dry them at 55±5°C. Turn the oven over every 2 hours. Use a rapid moisture meter to control the moisture content to below 3% to obtain dry granules.

[0245] A4: Granulation: Pass the dried granules through a 20-mesh sieve;

[0246] A5: Mixing: After granulation, add the prescribed amount of talc and low-substituted hydroxypropyl cellulose to obtain aspirin granules.

[0247] Codeine phosphate granules preparation:

[0248] B1: Equal-amount incremental mixing: Using the equal-amount incremental mixing method, weigh the prescribed amount of codeine phosphate hemihydrate, add an equal amount of beta-cyclodextrin, and mix evenly to obtain a mixture. Then, add an equal amount of beta-cyclodextrin to the mixture and mix evenly. Repeat this process until the prescribed amount of beta-cyclodextrin is added to obtain codeine phosphate mixed granules.

[0249] B2: Disintegrant mixing: Add the prescribed amount of low-substituted hydroxypropyl cellulose and talc to the codeine phosphate mixed granules and mix well to obtain codeine phosphate granules;

[0250] Tablet pressing:

[0251] (1) First, the prescribed amount of aspirin granules is placed into a tablet press to form aspirin tablets (slightly loose);

[0252] (2) Spread the prescribed amount of starch evenly until the aspirin tablet completely covers the surface, and press the tablet again (slightly loose);

[0253] (3) Add codeine phosphate granules to the starch layer, adjust the tablet press to a tablet hardness of 40 to 70 N after tableting, and punch a 14 mm die to obtain codeine phosphate and aspirin compound tablets.

[0254] Comparative Example 4 The raw materials and composition of codeine phosphate and aspirin compound tablets are shown in Table 10.

[0255] Table 10 Comparative Example 4 Codeine Phosphate and Aspirin Compound Tablets Raw Materials and Composition

[0256]

[0257] Comparative Example 5

[0258] Aspirin granules preparation:

[0259] A1: Premixing: Add aspirin, starch, and citric acid into a high shear wet granulator and stir until evenly mixed.

[0260] A2: Wet granulation: 8% starch slurry was added at a constant speed and the stirring blade and cutter were turned on to granulate to obtain wet granules (stirring speed: 300 rpm, shear speed: 1000 rpm, granulation time: 1 min);

[0261] A3: Drying: Transfer the wet granules to an oven and dry them at 55±5°C. Turn the oven over every 2 hours. Use a rapid moisture meter to control the moisture content to below 3% to obtain dry granules.

[0262] A4: Granulation: Pass the dried granules through a 20-mesh sieve;

[0263] A5: Mixing: After granulation, add the prescribed amount of talc and low-substituted hydroxypropyl cellulose to obtain aspirin granules.

[0264] Codeine phosphate granules preparation:

[0265] B1: Equal-amount incremental mixing: Using the equal-amount incremental mixing method, weigh the prescribed amount of codeine phosphate hemihydrate, add an equal amount of beta-cyclodextrin, and mix evenly to obtain a mixture. Then, add an equal amount of beta-cyclodextrin to the mixture and mix evenly. Repeat this process until the prescribed amount of beta-cyclodextrin is added to obtain codeine phosphate mixed granules.

[0266] B2: Disintegrant mixing: Add the prescribed amount of low-substituted hydroxypropyl cellulose and talc to the codeine phosphate mixed granules and mix well to obtain codeine phosphate granules;

[0267] Tablet pressing:

[0268] (1) First, the prescribed amount of aspirin granules is placed into a tablet press to form aspirin tablets (slightly loose);

[0269] (2) Spread the prescribed amount of starch evenly until the aspirin tablet completely covers the surface, and press the tablet again (slightly loose);

[0270] (3) Add codeine phosphate granules to the starch layer, adjust the tablet press to a tablet hardness of 40 to 70 N after tableting, and punch a 14 mm die to obtain codeine phosphate and aspirin compound tablets.

[0271] Comparative Example 5 The raw materials and composition of codeine phosphate and aspirin compound tablets are shown in Table 11.

[0272] Table 11 Comparative Example 5 Codeine Phosphate and Aspirin Compound Tablets Raw Materials and Composition

[0273]

[0274] Comparative Example 6

[0275] Aspirin granules preparation:

[0276] A1: Premixing: Add aspirin, starch, and citric acid into a high shear wet granulator and stir until evenly mixed.

[0277] A2: Wet granulation: 8% starch slurry was added at a constant speed and the stirring blade and cutter were turned on to granulate to obtain wet granules (stirring speed: 300 rpm, shear speed: 1000 rpm, granulation time: 1 min);

[0278] A3: Drying: Transfer the wet granules to an oven and dry them at 55±5°C. Turn the oven over every 2 hours. Use a rapid moisture meter to control the moisture content to below 3% to obtain dry granules.

[0279] A4: Granulation: Pass the dried granules through a 20-mesh sieve;

[0280] A5: Mixing: After granulation, add the prescribed amount of talc and low-substituted hydroxypropyl cellulose to the aspirin granules to obtain aspirin mixed granules.

[0281] Codeine phosphate granules preparation:

[0282] B1: Equal-amount incremental mixing: Using the equal-amount incremental mixing method, weigh the prescribed amount of codeine phosphate hemihydrate, add an equal amount of beta-cyclodextrin, and mix evenly to obtain a mixture. Then, add an equal amount of beta-cyclodextrin to the mixture and mix evenly. Repeat this process until the prescribed amount of beta-cyclodextrin is added to obtain codeine phosphate mixed granules.

[0283] B2: Disintegrant mixing: Add the prescribed amount of low-substituted hydroxypropyl cellulose and talc to the codeine phosphate mixed granules and mix well to obtain codeine phosphate granules;

[0284] Tablet pressing:

[0285] (1) First, the prescribed amount of aspirin granules is placed into a tablet press to form aspirin tablets (slightly loose);

[0286] (2) Spread the prescribed amount of starch evenly until the aspirin tablet completely covers the surface, and press the tablet again (slightly loose);

[0287] (3) Add codeine phosphate granules to the starch layer, adjust the tablet press to a tablet hardness of 40 to 70 N after tableting, and punch a 14 mm die to obtain codeine phosphate and aspirin compound tablets.

[0288] Comparative Example 6 The raw materials and composition of codeine phosphate and aspirin compound tablets are shown in Table 12.

[0289] Table 12 Comparative Example 6 Codeine Phosphate and Aspirin Compound Tablets Raw Materials and Composition

[0290]

[0291] The codeine phosphate and aspirin compound tablets prepared in Example 1 and Example 6, and the codeine phosphate and aspirin tablets prepared in Comparative Example 1 and Comparative Example 2 were subjected to stability tests at 0 days and high temperature for 10 days, respectively. Three parallel samples were set for each test. The stability test results are shown in Table 13.

[0292] The staking conditions for 10 days at high temperature are: placing at a temperature of 60°C for 10 days.

[0293] Table 13 Stability test results of Example 1, Example 6 and Comparative Examples 1-2

[0294]

[0295]

[0296] As shown in Table 13, under the same accelerated conditions, the degradation rate of the active ingredient of the codeine phosphate and aspirin compound tablets prepared by the three-layer preparation process of the present invention is significantly lower than that of the direct mixing preparation process, indicating that the codeine phosphate and aspirin compound tablets prepared by the three-layer preparation process of the present invention have better chemical stability. In the present invention, the codeine phosphate and aspirin compound tablets prepared using codeine phosphate hemihydrate as the raw material have better chemical stability than the codeine phosphate and aspirin compound tablets prepared using codeine phosphate sesquihydrate as the raw material.

[0297] After 10 days of high-temperature acceleration, the dissolution rate of the codeine phosphate and aspirin compound tablet sample prepared by the three-layer preparation process of the present invention did not change significantly compared with the initial dissolution rate, while the dissolution rate of the direct mixing process sample decreased significantly, indicating that the three-layer preparation process of the present invention has better physical stability.

[0298] The present invention also investigated the effect of disintegrant content on the active ingredients and dissolution rate of the compound tablets. A comparison of the raw material compositions of Examples 1-3 and Comparative Examples 3-4 is shown in Table 14, and the effects of different disintegrant contents on the stability of the compound tablets are shown in Table 15. As shown in Table 15, a 1%-2% reduction in disintegrant content significantly reduces the dissolution rate of codeine phosphate and aspirin, thereby reducing the efficacy.

[0299] Table 14 Comparison of raw material composition of Examples 1-3 and Comparative Examples 3-4

[0300]

[0301] Table 15 Effect of different disintegrant contents on the stability of compound tablets

[0302]

[0303] The present invention also investigated the effect of binder content on the active ingredients and dissolution of the compound tablets. A comparison of the raw material compositions of Example 1, Examples 4-5, and Comparative Examples 5-6 is shown in Table 16, and the results of the effects of different binder contents on the stability of the compound tablets are shown in Table 17. As shown in Table 17, increasing the binder content by 2% to 3% significantly reduces the dissolution of codeine phosphate and aspirin, thereby reducing the efficacy.

[0304] Table 16 Comparison of raw material composition of Example 1, Examples 4-5 and Comparative Examples 5-6

[0305]

[0306]

[0307] Table 17 Effect of different binder contents on the stability of compound tablets

[0308]

[0309] Example 7

[0310] Aspirin granules preparation:

[0311] A1: Premixing: Add aspirin, starch, and citric acid into a high shear wet granulator and stir until evenly mixed.

[0312] A2: Wet granulation: 8% starch slurry was added at a constant speed and the stirring blade and cutter were turned on to granulate to obtain wet granules (stirring speed: 200 rpm, shear speed: 800 rpm, granulation time: 1 min);

[0313] A3: Drying: Transfer the wet granules to an oven and dry them at 55±5°C. Turn the oven over every 2 hours. Use a rapid moisture meter to control the moisture content to below 3% to obtain dry granules.

[0314] A4: Granulation: Pass the dried granules through a 20-mesh sieve;

[0315] A5: Mixing: After granulation, add the prescribed amount of talc and low-substituted hydroxypropyl cellulose to obtain aspirin granules.

[0316] Codeine phosphate granules preparation:

[0317] B1: Equal-amount incremental mixing: Using the equal-amount incremental mixing method, weigh the prescribed amount of codeine phosphate hemihydrate, add an equal amount of beta-cyclodextrin, and mix evenly to obtain a mixture. Then, add an equal amount of beta-cyclodextrin to the mixture and mix evenly. Repeat this process until the prescribed amount of beta-cyclodextrin is added to obtain codeine phosphate mixed granules.

[0318] B2: Disintegrant mixing: Add the prescribed amount of low-substituted hydroxypropyl cellulose and talc to the codeine phosphate mixed granules and mix well to obtain codeine phosphate granules;

[0319] Tablet pressing:

[0320] (1) First, the prescribed amount of aspirin granules is placed into a tablet press to form aspirin tablets (slightly loose);

[0321] (2) Spread the prescribed amount of starch evenly until the aspirin tablet completely covers the surface, and press the tablet again (slightly loose);

[0322] (3) Add codeine phosphate granules to the starch layer, adjust the tablet press to a tablet hardness of 40 to 70 N after tableting, and punch a 14 mm die to obtain codeine phosphate and aspirin compound tablets.

[0323] The raw materials and composition of the codeine phosphate and aspirin compound tablets of Example 7 are shown in Table 18.

[0324] Table 18 Example 7 Codeine Phosphate and Aspirin Compound Tablet Raw Materials and Composition

[0325]

[0326] Example 8

[0327] Aspirin granules preparation:

[0328] A1: Premixing: Add aspirin, starch, and citric acid into a high shear wet granulator and stir until evenly mixed.

[0329] A2: Wet granulation: 8% starch slurry was added at a constant speed and the stirring blade and cutter were turned on to granulate to obtain wet granules (stirring speed: 400 rpm, shear speed: 1200 rpm, granulation time: 2 min);

[0330] A3: Drying: Transfer the wet granules to an oven and dry them at 55±5°C. Turn the oven over every 2 hours. Use a rapid moisture meter to control the moisture content to below 3% to obtain dry granules.

[0331] A4: Granulation: Pass the dried granules through a 20-mesh sieve;

[0332] A5: Mixing: After granulation, add the prescribed amount of talc and low-substituted hydroxypropyl cellulose to obtain aspirin granules.

[0333] Codeine phosphate granules preparation:

[0334] B1: Equal-amount incremental mixing: Using the equal-amount incremental mixing method, weigh the prescribed amount of codeine phosphate hemihydrate, add an equal amount of beta-cyclodextrin, and mix evenly to obtain a mixture. Then, add an equal amount of beta-cyclodextrin to the mixture and mix evenly. Repeat this process until the prescribed amount of beta-cyclodextrin is added to obtain codeine phosphate mixed granules.

[0335] B2: Disintegrant mixing: Add the prescribed amount of low-substituted hydroxypropyl cellulose and talc to the codeine phosphate mixed granules and mix well to obtain codeine phosphate granules;

[0336] Tablet pressing:

[0337] (1) First, the prescribed amount of aspirin granules is placed into a tablet press to form aspirin tablets (slightly loose);

[0338] (2) Spread the prescribed amount of starch evenly until the aspirin tablet completely covers the surface, and press the tablet again (slightly loose);

[0339] (3) Add codeine phosphate granules to the starch layer, adjust the tablet press to a tablet hardness of 40 to 70 N after tableting, and punch a 14 mm die to obtain codeine phosphate and aspirin compound tablets.

[0340] The raw materials and composition of the codeine phosphate and aspirin compound tablets of Example 8 are shown in Table 19.

[0341] Table 19 Example 8 Codeine Phosphate and Aspirin Compound Tablet Raw Materials and Composition

[0342]

[0343] Table 20 Results of the effects of different preparation processes on quality

[0344]

[0345] The present invention also investigates the effects of different preparation processes on the effective ingredients and dissolution of the compound tablets. The main component content and dissolution of the compound tablets prepared in Example 1 and Example 7-8 are shown in Table 20. As shown in Table 20, the codeine phosphate content and aspirin content of the compound tablets prepared in Example 1 and Example 7-8 all meet acceptable standards. The dissolution average value of Example 1 is the highest (codeine phosphate dissolution average value 100.6%, aspirin dissolution average value 100.7%), which is closest to the ideal value, and the inter-sample variability is low. The dissolution average values ​​of Examples 7 and 8 are lower (codeine phosphate 96.7% in Example 7, codeine phosphate dissolution average value 97.1% in Example 8, aspirin dissolution average value 97.1% in Example 7, and aspirin dissolution average value 97.9%), but are still within an acceptable range. However, the dissolution variability of Examples 7 and 8 is higher, indicating that the process controllability is slightly worse than that of Example 1.

[0346] The above embodiments are only preferred implementation modes of the present invention and are only used to explain the present invention rather than to limit the present invention. Any changes, substitutions, modifications, etc. made by those skilled in the art without departing from the spirit of the present invention should fall within the scope of protection of the present invention.

Claims

1. A codeine phosphate and aspirin compound tablet, characterized in that: It includes a codeine phosphate layer, a starch layer and an aspirin layer, and the starch layer spatially isolates the codeine phosphate layer from the aspirin layer.

2. A codeine phosphate and aspirin compound tablet according to claim 1, characterized in that: The mass ratio of the codeine phosphate layer, the starch layer and the aspirin layer is 147.01-149.77:40:578.656-600.

368.

3. A codeine phosphate and aspirin compound tablet according to claim 1 or 2, characterized in that: The raw materials of the aspirin layer are calculated in parts by weight and include: The disintegrant 1 includes low-substituted hydroxypropyl cellulose; The raw materials of the codeine phosphate layer are calculated in parts by weight and include: The disintegrant 2 includes low-substituted hydroxypropyl cellulose.

4. A codeine phosphate and aspirin compound tablet according to claim 3, characterized in that: The adhesive comprises 8% starch slurry.

5. A codeine phosphate and aspirin compound tablet according to claim 3, characterized in that: The codeine phosphate includes codeine phosphate hemihydrate and / or codeine phosphate sesquihydrate.

6. A method for preparing a codeine phosphate and aspirin compound tablet according to any one of claims 1 to 5, comprising the following steps: (1) granulating aspirin and tableting to obtain an aspirin tablet; (2) adding starch to the aspirin sheet layer and pressing the sheet to obtain an aspirin sheet layer-starch layer; (3) Granulating the codeine phosphate, placing the codeine phosphate granules on the aspirin sheet layer-starch layer, and tableting, wherein the tablet hardness after tableting is 40-70N, to obtain a codeine phosphate and aspirin compound tablet.

7. The preparation method according to claim 6, characterized in that The granulation method of described aspirin comprises the following steps: A1: Mix aspirin, starch, and citric acid evenly; A2: Add the binder at a uniform speed to granulate to obtain aspirin wet granules; A3: Dry the wet aspirin granules to a moisture content of ≤3%, sieve, and granulate; A4: Add talc and disintegrant 2 to obtain aspirin granules; The granulation method of codeine phosphate comprises the following steps: B1: using an equal amount incremental mixing method, codeine phosphate and beta-cyclodextrin are uniformly mixed to obtain codeine phosphate mixed particles; B2: Add disintegrant 1 and talc to the codeine phosphate mixed granules, mix well, and obtain codeine phosphate granules.

8. The preparation method according to claim 6, characterized in that In step A2, the stirring speed of the granulation is 200-400 rpm; the shearing speed is 800-1200 rpm; and the granulation time is 1-2 min.

9. The preparation method according to claim 6, characterized in that In step A3, the drying temperature is 50-60° C.; in step A3, during the drying process, the wet granules are turned over every 2 hours.

10. The preparation method according to claim 6, characterized in that In step A4, the sieving is through a 20-mesh sieve.

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