Rebamipide tablet as well as preparation method and application thereof

Abstract

The invention relates to the technical field of medicine preparation, and discloses a rebamipide tablet and a preparation method and application thereof, the rebamipide tablet comprises 40-60 parts of rebamipide, 3-6 parts of polyethylene glycol, 20-30 parts of beta-cyclodextrin, 5-8 parts of an adhesive, 10-20 parts of a filler, 2-5 parts of a disintegrating agent, 0.1-1 part of a flow aid, and 1-3 parts of a lubricant. According to the rebamipide tablet, beta-cyclodextrin and PEG are combined for use, so that the electrostatic adsorption phenomenon of rebamipide is weakened, agglomeration among rebamipide molecules is prevented, the flowability of rebamipide particles is improved, and the prepared rebamipide tablet is higher in particle uniformity and faster and higher in dissolution rate. In the preparation method, the beta-cyclodextrin is firstly added, stirred and sheared, the PEG solution is sprayed, then the adhesive, the filler, the disintegrating agent and the glidant are added, and the lubricant is added, so that the preparation process is relatively smooth, the yield is increased, the content uniformity of the rebamipide tablet is improved, the tablet weight difference is reduced, the dissolution rate is accelerated, and the bitter taste of the rebamipide is covered.

Description

Technical Field

[0001] The present invention relates to the technical field of drug preparation, and in particular to a rebamipide tablet and a preparation method and use thereof. Background Art

[0002] Rebamipide, chemical name: 2-(4-chlorobenzamide)-3-[2(1H)-quinolone-4-yl]propionic acid, is a drug that can protect the mucosa. It is commonly used clinically to treat gastric ulcers, acute gastritis, acute exacerbation of chronic gastritis leading to gastric mucosal erosion, bleeding, congestion, edema and other lesions.

[0003] Rebamipide is a BCS Class IV drug with low solubility and low permeability, and poor absorption in the body. Rebamipide is almost insoluble in water, sensitive to pH, insoluble under acidic conditions, and its solubility increases with increasing pH, and it has a certain degree of hygroscopicity. It is almost insoluble in the stomach, in a molecular state, with good permeability, and its solubility increases in the intestine, in an ionic state, with poor permeability, and low bioavailability.

[0004] During the preparation process, rebamipide has strong electrostatic effects, low bulk density, loose materials, and is difficult to granulate. It also tastes bitter, has low solubility, is not easy to disintegrate and dissolve, and its dissolution rate is difficult to be consistent with that of the original drug, resulting in unstable drug quality and no guarantee of clinical effectiveness and safety during administration. Summary of the invention

[0005] In view of this, in order to solve the problems that rebamipide has a loose texture, is difficult to granulate, and has a low solubility of the prepared tablets, the present invention provides a rebamipide tablet and a preparation method and use thereof. Experiments have shown that the preparation process of the rebamipide tablet is simple, the yield and solubility are high, and the dissolution rate is fast.

[0006] In a first aspect, the present invention provides a rebamipide tablet.

[0007] In an optional embodiment, the rebamipide tablets include the following raw and auxiliary materials by weight: 40-60 parts of rebamipide, 3-6 parts of polyethylene glycol, 20-30 parts of β-cyclodextrin, 5-8 parts of binder, 10-20 parts of filler, 2-5 parts of disintegrant, 0.1-1 part of glidant, and 1-3 parts of lubricant.

[0008] β-cyclodextrin is a type of cyclic oligosaccharide formed by six or more (generally 6, 7, or 8) glucose molecules connected end to end, and has a cylindrical hollow structure. β-cyclodextrin is selected for granulation in the present application.

[0009] β-cyclodextrin and rebamipide are mixed together by high-speed stirring and shearing, so that part of the rebamipide API enters the cavity of cyclodextrin and is wrapped, and the electrostatic interaction between rebamipide molecules is weakened by isolation, and rebamipide can be effectively dispersed, and the phenomenon of intermolecular aggregation into balls is weakened, thereby accelerating the dissolution rate of rebamipide. Because rebamipide is difficult to dissolve, it dissolves slowly after aggregation, and because cyclodextrin is a sugar substance and is easy to dissolve, the inclusion compound formed by cyclodextrin can improve the solubility and bioavailability of rebamipide, and the formation of the inclusion compound can mask the bitter taste of rebamipide.

[0010] β-cyclodextrin and PEG are used together, and the PEG solution is used to wet the rebamipide that is not wrapped by cyclodextrin, so that it will not easily float away, because the water molecules in the solution can form a molecular bond with the rebamipide molecules. In addition, PEG has a significant lubricating effect, which can reduce the electrostatic adsorption of rebamipide molecules, reduce raw material losses, and reduce the risk of low content. At the same time, high molecular weight PEG has very good solubility and is also compatible with rebamipide, increasing the solubility of rebamipide, but the effect is not as good as β-cyclodextrin. In short, β-cyclodextrin can first wrap part of rebamipide in the premixing stage, and then the PEG solution can be used to treat the remaining rebamipide. The combined use of the two can effectively prevent the aggregation of rebamipide molecules, increase the solubility of rebamipide, accelerate the dissolution rate, improve bioavailability, avoid sticking to the pot wall and cutter during the granulation process, make granulation smoother, and reduce the risk of low content.

[0011] In an optional embodiment, β-cyclodextrin and polyethylene glycol are used in combination, and the ratio of β-cyclodextrin to polyethylene glycol is (5-8):1;

[0012] The molecular weight of polyethylene glycol is 4000-8000 Da.

[0013] And / or, the ratio of rebamipide to β-cyclodextrin is (1.5-2.5):1.

[0014] In an optional embodiment, the filler is microcrystalline cellulose;

[0015] And / or, the binder is hydroxypropyl cellulose;

[0016] And / or, the disintegrant is low-substituted hydroxypropyl cellulose;

[0017] and / or, the glidant is colloidal silicon dioxide;

[0018] And / or, the lubricant is magnesium stearate.

[0019] In an optional embodiment, the rebamipide tablet further comprises a coating;

[0020] The weight gain of the coating is 2.5-3.5% of the weight of the tablet;

[0021] and / or, the coating is a gastric soluble film coating;

[0022] Optionally, the coating comprises ingredients including Opadry and / or Synfil.

[0023] In an optional embodiment, the rebamipide tablet has a hardness of 70-110N, a tablet weight of 0.205-0.239g, and a diameter of 7-8mm.

[0024] In a second aspect, the present invention provides a method for preparing rebamipide tablets.

[0025] 1) mixing polyethylene glycol and water to form a polyethylene glycol solution; stirring and shearing rebamipide and β-cyclodextrin at high speed to form a premixed powder, and spraying the polyethylene glycol solution into the premixed powder while mixing to form a complex;

[0026] (2) adding a binder, a filler, a disintegrant and a glidant to the composite obtained in step (1), mixing them evenly, adding water to granulate, granulating to form wet granules, drying and granulating to form dry granules, adding a lubricant and mixing in a hopper mixer to form a mixture;

[0027] (3) Compressing the mixed granules to form the rebamipide tablets.

[0028] Or including the following steps:

[0029] S1. Mixing polyethylene glycol and water to form a polyethylene glycol solution; mixing rebamipide, β-cyclodextrin, a binder, a filler, a disintegrant and a glidant and stirring and shearing to form a premixed powder;

[0030] S2, spraying the polyethylene glycol solution into the premixed powder obtained in step S1, granulating, granulating to form wet granules, drying and granulating to form dry granules, adding a lubricant and mixing to form a mixture;

[0031] S3, compressing the mixture into tablets to form the rebamipide tablets.

[0032] In an optional embodiment, in step (1), the ratio of polyethylene glycol to water in the polyethylene glycol solution is (1-3):5;

[0033] And / or, when the polyethylene glycol solution is sprayed, the atomization pressure is 0.03-0.07 MPa and the peristaltic pump speed is 43-47 rpm.

[0034] In an optional embodiment, in step (2), the granules are manually sieved after adding water for granulation, the mesh number of the manual sieving sieve is 10-24 mesh, and the particle size of the dry granules is less than 1.0 mm;

[0035] And / or, during the drying process, the air inlet temperature is 55-65℃ and the air volume is 20-40m 3 / h, loss on drying <3%.

[0036] In an optional embodiment, a wet granulator, a fluidized bed and a hopper mixer are used in the entire preparation process;

[0037] The stirring speed of the high-speed stirring and shearing is 350-450rpm, the cutting speed is 1800-2200rpm, and the stirring time is 5-7min;

[0038] And / or, in step (1), when the polyethylene glycol solution is sprayed, the stirring speed is 180-220 rpm and the cutting speed is 700-900 rpm;

[0039] And / or, in step (2), the water-adding granulation includes a liquid spraying process and a granulation process, the stirring speed of the liquid spraying process is 150-250 rpm, and the cutting speed is 700-900 rpm; the stirring speed of the granulation process is 250-350 rpm, the cutting speed is 1400-1600 rpm, and the granulation time is 1-3 min.

[0040] In a third aspect, the present invention provides a pharmaceutical preparation.

[0041] In an optional embodiment, the pharmaceutical preparation includes the rebamipide tablets or the rebamipide tablets obtained by the preparation method.

[0042] In an optional embodiment, the pharmaceutical preparation further comprises a pharmaceutically acceptable excipient; wherein the excipient comprises one or more of a solvent, a solubilizer, a co-solvent, a binder, a disintegrant, and a coating material;

[0043] And / or, the dosage form of the pharmaceutical preparation is any one of tablets, capsules, and granules.

[0044] In a fourth aspect, the present invention provides a use of the rebamipide tablets or the rebamipide tablets obtained by the preparation method in the preparation of drugs for treating gastric diseases.

[0045] Compared with the prior art, the present invention has the following beneficial effects:

[0046] The present invention provides a rebamipide tablet, comprising the following raw material ingredients: 40-60 parts of rebamipide, 3-6 parts of polyethylene glycol, 20-30 parts of β-cyclodextrin, 5-8 parts of adhesive, 10-20 parts of filler, 2-5 parts of disintegrant, 0.1-1 parts of glidant, and 1-3 parts of lubricant. β-cyclodextrin is used to tightly wrap rebamipide, which changes the problem of loose texture and easy agglomeration of rebamipide, accelerates the dissolution rate, improves solubility and bioavailability, and can also cover the bitter taste of rebamipide; PEG solution (polyethylene glycol solution) is wetted, so that rebamipide not wrapped by cyclodextrin is not easily dispersed, and PEG has a significant lubricating effect, which can increase the fluidity of particles, reduce the electrostatic adsorption equipment of rebamipide molecules, reduce raw material loss, and reduce the risk of low content. At the same time, PEG has very good solubility, is also compatible with rebamipide, and increases the solubility of rebamipide. The combined use of β-cyclodextrin and PEG increases the fluidity of rebamipide particles, prevents the raw material molecules from agglomerating into balls, and makes the particles in the prepared rebamipide tablets more uniform and dissolve more quickly.

[0047] The present invention provides a preparation method of rebamipide tablets, wherein β-cyclodextrin is first added to wrap rebamipide, thereby avoiding the problem of loose raw materials; PEG is then sprayed into the premixed powder to weaken the electrostatic adsorption of the unwrapped rebamipide, thereby improving the fluidity and uniformity of the particles and avoiding agglomeration; a lubricant is added after adding an adhesive, a filler, a disintegrant and a glidant to improve the formability and stability of the particles. The above preparation method is simple to granulate, and can effectively solve the problems of electrostatic adsorption, looseness, high viscosity, difficulty in granulation, slow dissolution, low bioavailability and bitter taste of rebamipide in the existing preparation process, thereby improving the particle fluidity, content uniformity and dissolution of the rebamipide tablets, while masking the bitterness of rebamipide in the rebamipide tablets. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 This is a sampling location diagram for the premixed powder of Example 1 or the mixed powder before spraying of Comparative Example 5. DETAILED DESCRIPTION

[0049] The following examples are provided for a better understanding of the present invention, but are not intended to limit the best mode of implementation, nor to limit the content and protection scope of the present invention. Any product identical or similar to the present invention obtained by anyone under the inspiration of the present invention or by combining the features of the present invention with other prior arts shall fall within the protection scope of the present invention.

[0050] Unless otherwise specified or incompatible herewith, the terms and phrases used herein shall have the following meanings:

[0051] In the present invention, the selection scope of "and / or" includes any one of two or more related listed items, and also includes any and all combinations of related listed items, and the said any and all combinations include any combination of two related listed items, any more related listed items, or all related listed items. For example, "A and / or B" includes three parallel solutions of A, B and A+B.

[0052] In the present invention, "plurality", "multiple", "multiple times", etc., unless otherwise specified, refer to a number greater than 2 or equal to 2. For example, "one or more" means one or greater than or equal to two.

[0053] In the present invention, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0054] In the present invention, when it comes to percentage content, unless otherwise specified, for solid-liquid mixing and solid-solid mixing, it refers to mass percentage, and for liquid-liquid mixing, it refers to volume percentage.

[0055] In the present invention, wt% refers to weight percentage, and vol% refers to volume percentage.

[0056] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0057] The present invention is further described in detail below in conjunction with specific embodiments. These embodiments should not be construed as limiting the scope of protection claimed by the present invention.

[0058] If no specific experimental steps or conditions are specified in the following experiments, the conventional experimental steps or conditions described in the literature in this field can be used. If no manufacturer is specified for the reagents or instruments used, they are all conventional reagent products that can be purchased commercially.

[0059] Rebamipide used in the following experiments was purchased from Zhengji Pharmaceutical Co., Ltd.;

[0060] Polyethylene glycol was purchased from Nanjing Well Pharmaceutical Co., Ltd., model PEG4000-PEG8000;

[0061] β-Cyclodextrin was purchased from Hunan Jiudian Hongyang Pharmaceutical Co., Ltd.

[0062] The dissolution apparatus was purchased from Jiangsu Fucosi Technology Co., Ltd., FODT-601 fiber optic dissolution apparatus.

[0063] Example 1

[0064] The present embodiment provides a rebamipide tablet, wherein the raw materials and auxiliary materials include: 450.0 g rebamipide, 250.0 g β-cyclodextrin, 45.0 g PEG6000, 140.0 g microcrystalline cellulose, 60.0 g hydroxypropyl cellulose, 30.0 g low-substituted hydroxypropyl cellulose, 5.0 g colloidal silicon dioxide, and 18.6 g magnesium stearate (calculated based on the weight of the particles obtained by dry granulation, the dosage is 2%);

[0065] The preparation method of rebamipide tablets is as follows:

[0066] (1) PEG was dissolved in 112.5 g of water to form a PEG solution; rebamipide and β-cyclodextrin were added to a wet granulation pot and mixed to form a premixed powder (partial inclusion complex), the stirring speed was 400 rpm, the cutting speed was 2000 rpm, and the mixing was performed for 5 min. The rebamipide content uniformity of the premixed powder was measured by sampling. The sampling position was as follows: Figure 1 ;

[0067] The PEG solution was sprayed in to wet rebamipide and β-cyclodextrin, with a stirring speed of 200 rpm, a cutter speed of 800 rpm, an atomization pressure of 0.05 MPa, and a peristaltic pump speed of 45 rpm to form a complex (complete inclusion complex);

[0068] (2) adding microcrystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, and colloidal silicon dioxide, stirring at a speed of 150 rpm and a cutting speed of 400 rpm, and mixing for 3 minutes;

[0069] 187.5 g of water was used to prepare the soft material. In the spraying process, the stirring speed was 200 rpm, the cutting speed was 800 rpm, the atomizing pressure was 0.05 MPa, and the peristaltic pump speed was 45 rpm. In the granulation process, the stirring speed was 300 rpm, the cutting speed was 1500 rpm, and the granulation was 2 min. Then, a 10-mesh screen was used for wet granulation. The fluidized bed was dried with an inlet air temperature of 55-65 ° C and an air volume of 20-40 m 3 / h, drying loss 1.97%; dry granules 1.0mm sieve, mixing speed 800rpm; get dry granules 911.5g, add magnesium stearate for mixing, mixing speed 8rpm, mixing time 5min;

[0070] (3) Tableting: tablet weight was controlled at 0.205-0.239 g, hardness was controlled at 70-110 N, and tablet diameter was 7.5 mm; coating (Opadry) was applied: coating weight gain was controlled at 3%±0.5%.

[0071] Example 2

[0072] This embodiment provides a rebamipide tablet, wherein the raw materials and auxiliary materials include 450.0 g of rebamipide, 200.0 g of β-cyclodextrin, 60.0 g of PEG6000, 175.0 g of microcrystalline cellulose, 60.0 g of hydroxypropyl cellulose, 30.0 g of low-substituted hydroxypropyl cellulose, 5.0 g of colloidal silicon dioxide, and 18.3 g of magnesium stearate;

[0073] The preparation method of rebamipide tablets is as follows:

[0074] (1) Dissolve PEG in 150.0 g of water to form a PEG solution; add rebamipide and β-cyclodextrin into a wet granulation pot and mix to form a premixed powder; stir at a speed of 350 rpm and a cutter at a speed of 2200 rpm and mix for 5 min;

[0075] The PEG solution was sprayed in to wet rebamipide and β-cyclodextrin, with a stirring speed of 220 rpm, a cutter speed of 700 rpm, an atomization pressure of 0.05 MPa, and a peristaltic pump speed of 45 rpm to form a complex;

[0076] (2) adding microcrystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, and colloidal silicon dioxide to the composite, stirring at a speed of 150 rpm and a cutting speed of 400 rpm, and mixing for 3 min;

[0077] 150.0 g of water was used to prepare the soft material. In the spraying process, the stirring speed was 150 rpm, the cutting speed was 900 rpm, the atomizing pressure was 0.03 MPa, and the peristaltic pump speed was 43 rpm. In the granulation process, the stirring speed was 250 rpm, the cutting speed was 1600 rpm, and the granulation time was 2 min. Then, the granules were manually sieved through a 10-mesh screen to form wet granules. The fluidized bed was dried with an inlet air temperature of 55-65° C. and an air volume of 20-40 m 3 / h, drying loss 2.13%; dry granules 1.0mm sieve, mixing speed 800rpm; get dry granules 896.2g, add magnesium stearate for mixing, mixing speed 8rpm, mixing time 5min;

[0078] (3) Tableting: tablet weight is controlled at 0.205-0.239 g, hardness is controlled at 70-110 N, and tablet diameter is 7.5 mm;

[0079] Coating (New Phil), control the coating weight gain to 3% ± 0.5%.

[0080] Example 3

[0081] This embodiment provides a rebamipide tablet, wherein the raw materials and auxiliary materials include 450.0 g of rebamipide, 300.0 g of β-cyclodextrin, 40.0 g of PEG6000, 105.0 g of microcrystalline cellulose, 50.0 g of hydroxypropyl cellulose, 30.0 g of low-substituted hydroxypropyl cellulose, 5.0 g of colloidal silicon dioxide, and 18.1 g of magnesium stearate;

[0082] The preparation method of rebamipide tablets is as follows:

[0083] Dissolve PEG in 200.0 g of water to form a PEG solution; add rebamipide and β-cyclodextrin into a wet granulation pot and mix to form a premixed powder, stir at 450 rpm, cutter at 1800 rpm, and mix for 7 min;

[0084] The PEG solution was sprayed in to wet rebamipide and β-cyclodextrin, with a stirring speed of 180 rpm, a cutter speed of 900 rpm, an atomization pressure of 0.07 MPa, and a peristaltic pump speed of 47 rpm to form a complex;

[0085] (2) Add microcrystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, and colloidal silicon dioxide, stir at a speed of 150 rpm, cutter at a speed of 400 rpm, and mix for 3 minutes; use 100.0 g of water to prepare the soft material, wherein, in the spraying process, the stirring speed is 250 rpm, the cutter speed is 700 rpm, the atomization pressure is 0.05 MPa, and the peristaltic pump speed is 45 rpm; in the granulation process, the stirring speed is 350 rpm, the cutter speed is 1400 rpm, and the granulation is 2 minutes; then use a 10-mesh screen to wet granulate; fluidized bed drying, the inlet air temperature is 55-65°C, the air volume is 20-40 m 3 / h, drying loss 1.77%; dry granulation 1.0mm sieve, 800rpm; get dry granulation 885.7g, add magnesium stearate for mixing, mixing speed 8rpm, mixing time 5min;

[0086] (3) Tableting: tablet weight was controlled at 0.205-0.239 g, hardness was controlled at 70-110 N, and tablet diameter was 7.5 mm; coating (Opadry and Synfil were mixed at a weight ratio of 1:1), and the coating weight gain was controlled at 3%±0.5%.

[0087] Example 4

[0088] This embodiment provides a rebamipide tablet, the raw materials comprising: 450.0 g rebamipide, 250.0 g β-cyclodextrin, 45.0 g PEG6000, 140.0 g microcrystalline cellulose, 60.0 g hydroxypropyl cellulose, 30.0 g low-substituted hydroxypropyl cellulose, 5.0 g colloidal silicon dioxide, and 18.6 g magnesium stearate;

[0089] The preparation method of rebamipide tablets is as follows:

[0090] (1) Dissolve PEG in 300.0 g purified water to form a PEG solution; add rebamipide, β-cyclodextrin, microcrystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, and colloidal silicon dioxide into a wet granulation pot and mix to form a premixed powder; stir at a speed of 400 rpm and a cutter at a speed of 2000 rpm and mix for 5 min;

[0091] (2) PEG solution was used to prepare the soft material. In the spraying process, the stirring speed was 200 rpm, the cutting speed was 800 rpm, the atomization pressure was 0.05 MPa, and the peristaltic pump speed was 45 rpm. In the granulation process, the stirring speed was 300 rpm, the cutting speed was 1500 rpm, and the granulation time was 2 min. Then, the granules were wet granulated with a 10-mesh screen. The fluidized bed was dried with an inlet air temperature of 55-65°C and an air volume of 20-40 m 3 / h, drying loss 1.65%; dry granulation 1.0mm sieve, 800rpm; get dry granulation 860.8g, add magnesium stearate for mixing, mixing speed 8rpm, mixing time 5min;

[0092] (3) Tableting: tablet weight is controlled at 0.205-0.239 g, hardness is controlled at 70-110 N, and tablet diameter is 7.5 mm;

[0093] Coating: control coating weight gain to 3%±0.5%.

[0094] Comparative Example 1

[0095] This comparative example provides a rebamipide tablet, without adding cyclodextrin and PEG, and the raw materials and auxiliary materials include: 450.0g rebamipide, 435.0g microcrystalline cellulose, 60.0g hydroxypropyl cellulose, 30.0g low-substituted hydroxypropyl cellulose, and 5.0g colloidal silicon dioxide;

[0096] The preparation method of rebamipide tablets is as follows:

[0097] Add rebamipide, microcrystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, and colloidal silicon dioxide into a wet granulation pot and mix to form a premixed powder. Stir at a speed of 150 rpm and a cutter at a speed of 400 rpm for 3 minutes.

[0098] 300.0 g of purified aqueous solution was used to prepare the soft material. During the spraying process, the stirring speed was 150 rpm, the cutter speed was 900 rpm, the atomization pressure was 0.03 MPa, and the peristaltic pump speed was 43 rpm. During the liquid addition process, the torque of the wet granulator gradually increased due to the sticking of the material to the bottom, and the experiment could not continue.

[0099] Comparative Example 2

[0100] This comparative example provides a rebamipide tablet without adding β-cyclodextrin, and the raw materials and auxiliary materials include: 450.0g rebamipide, 45.0g PEG6000, 390.0g microcrystalline cellulose, 60.0g hydroxypropyl cellulose, 30.0g low-substituted hydroxypropyl cellulose, 5.0g colloidal silicon dioxide, and 18.6g magnesium stearate;

[0101] The preparation method of rebamipide tablets is as follows:

[0102] Dissolve PEG in 150.0 g of water to form a PEG solution; add rebamipide and microcrystalline cellulose to a wet granulation pot and mix to form a premixed powder, stir at a speed of 350 rpm, a cutter speed of 2200 rpm, and mix for 5 min; wet rebamipide and microcrystalline cellulose with the PEG solution, stir at a speed of 220 rpm, a cutter speed of 700 rpm, an atomization pressure of 0.05 MPa, and a peristaltic pump speed of 45 rpm to form a complex;

[0103] (2) Hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, and colloidal silicon dioxide were added to a wet granulation pot and mixed to form a premixed powder. The stirring speed was 150 rpm, the cutting speed was 400 rpm, and the mixing was performed for 3 min. 150.0 g of purified water was used to prepare the soft material. In the spraying process, the stirring speed was 200 rpm, the cutting speed was 800 rpm, the atomization pressure was 0.05 MPa, and the peristaltic pump speed was 45 rpm. In the granulation process, the stirring speed was 300 rpm, the cutting speed was 1500 rpm, and the granulation was performed for 2 min. Then, a 10-mesh screen was used for wet granulation. Fluidized bed drying was performed with an inlet air temperature of 55-65°C and an air volume of 20-40 m 3 / h, drying loss 1.86%; dry granulation 1.0mm sieve, 800rpm; get dry granulation 834.7g, add magnesium stearate for mixing, mixing speed 8rpm, mixing time 5min;

[0104] (3) Tableting: tablet weight is controlled at 0.205-0.239 g, hardness is controlled at 70-110 N, and tablet diameter is 7.5 mm;

[0105] Coating: control coating weight gain to 3%±0.5%.

[0106] Comparative Example 3

[0107] This comparative example provides a rebamipide tablet without adding PEG, and the raw materials include: 450.0g rebamipide, 250.0g β-cyclodextrin, 185.0g microcrystalline cellulose, 60.0g hydroxypropyl cellulose, 30.0g low-substituted hydroxypropyl cellulose, 5.0g colloidal silicon dioxide, and 18.6g magnesium stearate;

[0108] The preparation method of rebamipide tablets is as follows:

[0109] Add rebamipide and β-cyclodextrin into a wet granulation pot and mix to form a premixed powder, stir at a speed of 350 rpm, cutter at a speed of 2200 rpm, and mix for 5 min; wet rebamipide and β-cyclodextrin with 200.0 g purified water, stir at a speed of 220 rpm, cutter at a speed of 700 rpm, atomization pressure of 0.05 MPa, and peristaltic pump at a speed of 45 rpm to form a complex;

[0110] (2) Add microcrystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, and colloidal silicon dioxide, stir at a speed of 150 rpm, cutter at a speed of 400 rpm, and mix for 3 minutes; use 100.0 g of water to prepare the soft material, wherein, in the spraying process, the stirring speed is 200 rpm, the cutter speed is 800 rpm, the atomization pressure is 0.05 MPa, and the peristaltic pump speed is 45 rpm; in the granulation process, the stirring speed is 300 rpm, the cutter speed is 1500 rpm, and the granulation is 2 minutes; then use a 10-mesh screen to wet granulate; fluidized bed drying, the inlet air temperature is 55-65°C, the air volume is 20-40 m 3 / h, drying loss 2.08%; dry granulation 1.0mm sieve, 800rpm; get dry granulation 816.3g, add magnesium stearate for mixing, mixing speed 8rpm, mixing time 5min;

[0111] (3) Tableting: the tablet weight is controlled at 0.205-0.239 g, the hardness is controlled at 70-110 N, and the tablet diameter is 7.5 mm;

[0112] Coating: control coating weight gain to 3%±0.5%.

[0113] Comparative Example 4

[0114] The present comparative example provides a rebamipide tablet, which adopts the raw materials and preparation method of CN117122572A, and the raw materials include: 100g rebamipide, 85.71g glyceryl behenate, 34.29g poloxamer, 50g microcrystalline cellulose, 2.49g hydroxypropyl cellulose, 0.31g polyethylene glycol, 20g low-substituted hydroxypropyl cellulose, 1g magnesium stearate and an appropriate amount of purified water.

[0115] The preparation method is as follows:

[0116] Prepare a 10% hydroxypropyl cellulose and polyethylene glycol solution, slowly add the prescribed amount of hydroxypropyl cellulose and polyethylene glycol into a beaker containing the prescribed amount of purified water (room temperature), stirring while adding, and continue stirring for 20 minutes after the addition is completed, with a stirring speed of 500 rpm (two-blade paddle), and after the stirring is completed, low-substituted hydroxypropyl cellulose is formed, which is set aside;

[0117] Rebamipide, microcrystalline cellulose, glyceryl behenate and poloxamer were placed in a granulator, and the raw materials and auxiliary materials were preheated. The fan frequency was 25-30 Hz. When the material temperature reached 40-42 ° C, spray granulation was started (before spraying, the mixed powder was taken to measure the uniformity of rebamipide content, and the sampling position was as follows: Figure 1 ); Due to the uniformity of content, the material temperature is lowered, and it needs to be reheated to 40-42℃ for spray granulation, the air inlet temperature is 60±10℃, and the fan frequency is 25-30Hz; the material temperature is ≤50℃, and the liquid supply speed is about 1.0g / min; the atomization pressure is 0.3MPa, and the particle moisture is controlled at 2.0%-4.0%; a Φ1.5mm screen is used for granulation, and the granulation frequency is 10.0Hz;

[0118] Add low-substituted hydroxypropyl cellulose and mix for 10 minutes at a mixing speed of 8 rpm; add magnesium stearate and mix for 5 minutes at a mixing speed of 8 rpm; use a Φ8.0 mm punch to press the tablet, and the tablet hardness is 30-50N.

[0119] Test Example 1

[0120] Detecting the bulk density of the premixed powders in Examples 1-4 and Comparative Examples 1-4;

[0121] Test method: According to the first fixed mass method of the Chinese Pharmacopoeia 2020 edition, take about 100 g of the powder sample to be tested (if necessary, it should be passed through a sieve with a pore size of 1.0 mm to fully disperse the lumps formed during storage. The sieving operation should be gentle to avoid changing the properties of the powder), accurately weigh, slowly pour into a glass graduated cylinder, carefully scrape the top of the cup, avoid compacting the powder, record the apparent volume at the closest scale line, and calculate the bulk density according to the formula: ρ = M / V0, M represents the mass of the powder sample to be tested, and V0 represents the apparent volume.

[0122] The test results are shown in Table 1.

[0123] Table 1 Premixed powder bulk density

[0124]

[0125]

[0126] From the bulk density results, it can be seen that the use of β-cyclodextrin in Examples 1, 2, 3, 4 and Comparative Example 3 can increase the bulk density of the premixed powder. β-cyclodextrin can wrap the rebamipide raw material and solve its loose nature through the physical method of high-speed stirring and shearing.

[0127] Test Example 2

[0128] Detecting the uniformity of the rebamipide content in the premixed powders in Example 1 and Comparative Example 4;

[0129] Sampling method: After premixing, sample 10 points in the upper, middle and lower layers, numbered 1-10 (see Figure 1 , points 1-4 are the upper layer, 5-7 are the middle layer, and 8-10 are the bottom layer), about 0.4g is sampled at each point (0.8ml sampler), and 3 parallel samples are taken from each sampling point to determine the content uniformity of the premixed powder.

[0130] Detection method: According to the national drug standard tablet determination method, high performance liquid chromatography was used for determination. The chromatographic column was filled with octadecylsilane bonded silica gel. The mobile phase was acetonitrile-phosphate solution (0.58g of anhydrous disodium hydrogen phosphate + 2.0g of potassium dihydrogen phosphate, add water to 1000ml) = 17:83, and the detection wavelength was 254nm.

[0131] Acceptable standard for uniformity of premixed powder content: test the content of one sample at each sampling point and calculate the RSD of all samples (n=10).

[0132] ① If RSD≤5.0% (n=10), the mixing uniformity of the premixing process of the batch of samples is acceptable;

[0133] ② If RSD>5.0% (n=10), measure the premix uniformity of the remaining samples (10 sampling points with 2 remaining samples n=20). Further determination is as follows: measure the remaining samples at each sampling point (n=20) and calculate the RSD of all samples (n=30).

[0134] ③ If RSD ≤ 5.0% (n = 30), then conduct a mixing uniformity test in the mixing process (measure all sampling points in the mixing process).

[0135] ④ If RSD>5.0% (n=30), investigate to determine whether the variability is caused by product / process problems or sampling / assay errors.

[0136] Test results: The test results are shown in Table 2.

[0137] Table 2 Uniformity of rebamipide content in premixed powder

[0138]

[0139] From the content uniformity results of the premixed powders of Comparative Example 4 and Example 1, it can be seen that the content uniformity of the premixed powder of the present application is better. The content of the upper sampling point of Comparative Example 4 is higher than that of the lower sampling point, indicating that the preheating process in the fluidized bed is prone to stratification, and rebamipide is more likely to be blown into the upper layer.

[0140] Test Example 3 Preparation process

[0141] The results of observing whether there is sticking to the bottom, wall, or punching during the preparation of Examples 1-4 and Comparative Examples 1-4 are as follows:

[0142] Example 1: Granulation was relatively smooth, without sticking to the bottom, wall, or punching;

[0143] Example 2: Granulation was relatively smooth, without sticking to the bottom, wall, or punching;

[0144] Example 3: Granulation was relatively smooth, without sticking to the bottom, wall, or punching;

[0145] Example 4: During the granulation process, rebamipide is prone to agglomeration, pilling, uneven dispersion, and sticking to the wall;

[0146] Comparative Example 1: During the granulation process, the material pilling was serious, the bottom of the wet pan was easy to stick to the bottom, the torque became larger, affecting the operation of the equipment, and the test was stopped;

[0147] Comparative Example 2: The granulation was relatively smooth, with slight sticking to the bottom and wall, and no sticking;

[0148] Comparative Example 3: During the granulation process, the material slightly accumulated, adhered to the bottom, adhered to the wall, and pilled;

[0149] Comparative Example 4: During the preheating process, the API and other excipients were mixed unevenly, and it was observed that the API was seriously scattered, while the granulation was relatively smooth.

[0150] Through the preparation process, it was found that the raw material of rebamipide is very easy to stick. Examples 1-3 use a wet granulator to granulate, and the raw materials need to be processed. The combined use of cyclodextrin and PEG solution can effectively disperse rebamipide, isolate rebamipide from sticking to each other, ensure that the powder is fully wetted and effectively combined with cyclodextrin, and improve the formability and stability of the particles. Example 4 does not use PEG solution to wet rebamipide and β-cyclodextrin, which is easy to agglomerate, pilling, uneven dispersion, and sticky wall. Comparative Examples 1-3 do not use cyclodextrin or PEG, and are prone to sticking to the bottom, sticking to the wall, sticking to the wall, or accumulation during the preparation process; Comparative Example 4 does not use cyclodextrin and does not use the preparation method of the present application, so that the raw material drug and other excipients are not mixed evenly during the preheating process, and the raw material drug is seriously scattered.

[0151] Test 4: Flowability of mixed particles

[0152] Testing the fluidity of the mixed particles in Examples 1-4 and Comparative Examples 1-4;

[0153] Detection method: Injection method, slowly add the powder from the top of the funnel, and the material leaking from the bottom of the funnel forms a cone-shaped accumulation at an inclination angle on the horizontal plane.

[0154] Calculation formula: Where, H: cone height, R: cone base radius.

[0155] The test results are shown in Table 3.

[0156] Table 3 Flowability of mixed particles

[0157]

[0158] It can be seen from the repose angles of various tests that Examples 1, 2, 3, 4 and Comparative Example 2 use PEG, and the repose angles are smaller, indicating better fluidity. The addition of PEG in this application can increase the fluidity of the particles.

[0159] Difference in weight of 5 tablets tested

[0160] According to the Chinese Pharmacopoeia, the weight difference of tablets of 0.3 g or less is ±7.5%. Ten tablets of rebamipide tablets prepared in Examples 1-4 and Comparative Examples 1-4 were randomly taken from each sample and weighed. The results are shown in Table 4:

[0161] Table 4 Tablet weight

[0162]

[0163]

[0164] From the results in the above table, it can be seen that the tablet weight difference of Examples 1-3 of the present application is small, which is -2.25% to 1.35%, -1.23% to 1.97%, and -2.23% to 2.32%, respectively; the tablet weight difference of Comparative Examples 2-4 and Example 4 is large. Because the particles prepared in Examples 1, 2, and 3 have good fluidity and relatively uniform particle size, the tablet weight difference caused in the tableting process is small. On the contrary, although the fluidity of Comparative Example 2 and Example 4 is also good, the particle size is not uniform, and there is more fine powder, resulting in a large difference in tablet weight. Comparative Example 3 has the worst fluidity and the largest difference in the tablet. Comparative Example 4 has a slightly worse tablet weight difference than Examples 1-3. Because of the different preparation processes, the particles prepared in Comparative Example 4 are small, the fine powder is slightly more, and the tablet weight difference is slightly larger.

[0165] Test Example 6 Dissolution

[0166] The dissolution of the rebamipide tablets obtained in Examples 1-4 and Comparative Examples 1-4 was tested. The testing method was the slurry method in the General Rules of Part IV of the 2020 edition of the Chinese Pharmacopoeia. The specific method included: placing the rebamipide tablets in the Examples and Comparative Examples in 900 ml of buffer (the buffer was a phosphate buffer, and the pH value of the buffer was 6.0), respectively, stirring at 37°C at a stirring speed of 50 r / min for 60 min, and then testing the dissolution of the rebamipide tablets by a dissolution instrument. The test results are shown in Table 5 below.

[0167] Table 5 Dissolution

[0168]

[0169] It can be seen from the dissolution that Examples 1-3 have good solubility and fast release rate, while Example 4 is slightly inferior. The dissolution rate or dissolution rate of Comparative Examples 2-4 is slightly worse. Comparative Example 2 does not use β-cyclodextrin, which leads to sphering between the rebamipide raw materials, resulting in fast release on the surface of the spheres and slow release inside, so the dissolution rate is slow; Comparative Example 3 uses β-cyclodextrin and does not use PEG, and the dissolution rate is slightly better than that of Comparative Example 2, but the dissolution rate is low, because there is no PEG to increase the lubricity of the granulation process, and the sticky loss of the raw material is slightly more; Although both β-cyclodextrin and PEG are used in Example 4, PEG is added in the form of powder, the effect is not obvious, and the dissolution rate is also slightly low; Comparative Example 4 uses fluidized bed granulation, the raw materials are easily lost, and the dissolution rate is lower than that of wet granulation.

[0170] Obviously, the above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived therefrom are still within the scope of protection of the invention.

Claims

1. A rebamipide tablet, characterized in that: The rebamipide tablets include the following raw and auxiliary materials by weight: 40-60 parts of rebamipide, 3-6 parts of polyethylene glycol, 20-30 parts of β-cyclodextrin, 5-8 parts of binder, 10-20 parts of filler, 2-5 parts of disintegrant, 0.1-1 part of glidant, and 1-3 parts of lubricant.

2. The rebamipide tablet according to claim 1, characterized in that: β-cyclodextrin and polyethylene glycol should be used together, and the ratio of β-cyclodextrin to polyethylene glycol is (5-8):1; And / or, the ratio of rebamipide to β-cyclodextrin is (1.5-2.5):

1.

3. The rebamipide tablet according to claim 1 or 2, characterized in that: The filler is microcrystalline cellulose; And / or, the binder is hydroxypropyl cellulose; And / or, the disintegrant is low-substituted hydroxypropyl cellulose; and / or, the glidant is colloidal silicon dioxide; And / or, the lubricant is magnesium stearate.

4. The rebamipide tablet according to claim 1 or 2, characterized in that: The rebamipide tablet further comprises a coating; The weight of the coating is 2.5-3.5% of the weight of the tablet; and / or, the coating is a gastric soluble film coating; wherein the coating comprises Opadry and / or Synfil; And / or, the rebamipide tablet has a hardness of 70-110N, a tablet weight of 0.205-0.239g, and a diameter of 7-8mm.

5. A method for preparing the rebamipide tablets according to any one of claims 1 to 4, characterized in that: The preparation method comprises the following steps: (1) mixing polyethylene glycol and water to form a polyethylene glycol solution; stirring and shearing rebamipide and β-cyclodextrin to form a premixed powder, and spraying the polyethylene glycol solution into the premixed powder while mixing to form a complex; (2) adding a binder, a filler, a disintegrant and a glidant to the composite obtained in step (1), mixing them evenly, adding water to granulate, granulating to form wet granules, drying and granulating to form dry granules, adding a lubricant and mixing to form a mixture; (3) compressing the mixture to form the rebamipide tablets; or The following steps are involved: S1. Mixing polyethylene glycol and water to form a polyethylene glycol solution; mixing rebamipide, β-cyclodextrin, a binder, a filler, a disintegrant and a glidant and stirring and shearing to form a premixed powder; S2, spraying the polyethylene glycol solution into the premixed powder obtained in step S1, granulating, granulating to form wet granules, drying and granulating to form dry granules, adding a lubricant and mixing to form a mixture; S3, compressing the mixture into tablets to form the rebamipide tablets.

6. The preparation method according to claim 5, characterized in that: In step (1), the ratio of polyethylene glycol to water in the polyethylene glycol solution is (1-3):5; And / or, when the polyethylene glycol solution is sprayed, the atomization pressure is 0.03-0.07 MPa and the peristaltic pump speed is 43-47 rpm.

7. The preparation method according to claim 5, characterized in that: In step (2), the granules are manually sieved after adding water for granulation, the mesh number of the manual sieving sieve is 10-24 mesh, and the particle size of the dry granules is less than 1.0 mm; And / or, during the drying process, the air inlet temperature is 55-65℃ and the air volume is 20-40m 3 / h, loss on drying <3%.

8. The preparation method according to claim 5, characterized in that: The stirring speed of the stirring and shearing is 350-450rpm, the cutting speed is 1800-2200rpm, and the stirring and shearing time is 5-7min; and / or, when the polyethylene glycol solution is sprayed, the stirring speed is 180-220 rpm and the cutting speed is 700-900 rpm; And / or, the water-adding granulation includes a liquid spraying process and a granulation process, the stirring speed of the liquid spraying process is 150-250rpm, and the cutting speed is 700-900rpm; the stirring speed of the granulation process is 250-350rpm, the cutting speed is 1400-1600rpm, and the granulation time is 1-3min.

9. A pharmaceutical preparation, characterized in that The pharmaceutical preparation comprises the rebamipide tablets according to any one of claims 1 to 4 or the rebamipide tablets obtained by the preparation method according to claims 5 to 8; The pharmaceutical preparation further includes pharmaceutically acceptable excipients; wherein the excipients include one or more of solvents, solubilizers, co-solvents, binders, disintegrants, and coating materials; And / or, the dosage form of the pharmaceutical preparation is any one of tablets, capsules, and granules.

10. Use of the rebamipide tablet according to any one of claims 1 to 4 or the rebamipide tablet obtained by the preparation method according to claims 5 to 8 in preparing a drug for treating gastric diseases.

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