Doxofylline tablet and preparation method thereof

Abstract

The invention discloses a doxofylline tablet and a preparation method thereof. The doxofylline tablet is prepared from the following raw materials in parts by weight: 35 to 50 parts of doxofylline, 10 to 20 parts of a filling agent, 3 to 9 parts of a flow aid, 1 to 4.35 parts of an adhesive, 0.05 to 0.4 part of a lubricating agent and 0.02 to 0.5 part of a disintegrating agent. The adhesive is povidone and / or copovidone; the disintegrating agent is cross-linked sodium carboxymethyl cellulose. The doxofylline tablet provided by the invention is similar to a reference preparation in dissolution, uniform in content, good in stability and relatively good in compressibility.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, and in particular to doxofylline tablets and a preparation method thereof. Background Art

[0002] This section merely provides background information related to the present disclosure and is not necessarily prior art.

[0003] Doxofylline is a derivative of methylxanthine. It is a bronchodilator that can directly act on the bronchi to relax tracheal smooth muscle. The chemical name of doxofylline is 1,3-dimethyl-7-(1,3-dioxacyclopentyl-2-yl)methyl-3,7-dihydro-1H-purine-2,6-dione; the molecular formula is C 11 H 14 N4O4; molecular weight is 266.26. Doxofylline can inhibit phosphodiesterase and is suitable for bronchial asthma, wheezing chronic bronchitis and other bronchial spasms caused by dyspnea. It has the characteristics of strong effect, long action time, rapid distribution, low toxicity and small side effects. Doxofylline tablets are a new generation of theophylline derivatives launched in Italy in 1984, with the trade name ANSIMAR and the licensee ABC Farmaceutici SPA.

[0004] Chinese patent application number CN105037361A discloses a doxofylline compound and its pharmaceutical composition, wherein the tablets are made of microcrystalline cellulose, sodium carboxymethyl cellulose, pregelatinized corn starch, lactose monohydrate and doxofylline, and then wet granulated with 6% povidone K30 ethanol solution as a binder, and then compressed into tablets after drying at 60°C for 5 hours. Lactose and doxofylline are directly in contact with each other to make soft materials, and the high temperature and high humidity environment of the drying step makes it easy to produce impurities during the preparation process. This leads to a decrease in solubility during the stability process. In addition, this patent disclosure requires drying for 5 hours, and the process preparation consumes a lot of energy and takes a long time.

[0005] Chinese patent application number CN101028254B ​​discloses a doxofylline sustained-release preparation and a preparation method thereof, wherein the immediate-release tablets are prepared by mixing lactose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, polyvinyl pyrrolidone ethanol solution K-30 with a part of the doxofylline soft material and then mixing with a lubricant. The doxofylline preparation disclosed in this disclosure has deficiencies in stability data, generates impurities during long-term storage, and reduces the content of the active ingredient.

[0006] Chinese patent application number CN110898019A discloses a doxofylline tablet and a preparation method thereof, comprising mixing silicon dioxide, mannitol, a disintegrant, sodium starch glycolate, and talcum powder to obtain a first mixture; mixing doxofylline and magnesium stearate to obtain a second mixture; mixing the first mixture with the second mixture to obtain a third mixture; and tableting the third mixture. The disclosed disintegrant uses microcrystalline cellulose, and the drug with a high viscosity will accumulate after disintegration, resulting in large variability in dissolution.

[0007] Through research and analysis, it is found that the disclosed doxofylline tablets and preparation methods thereof are insufficient in stability, and the dissolution rate is reduced during the stability process. The commercially available doxofylline tablets are insufficient in dissolution, and the dissolution variability is large. This is not conducive to the commercial production and clinical use of doxofylline tablets. It is necessary to develop a stable doxofylline tablet with a simple process and a preparation method thereof, which has better stability and dissolution rate. Summary of the invention

[0008] Purpose of the invention: The technical problem to be solved by the present invention is to provide a doxofylline tablet and a preparation method thereof in view of the deficiencies in the prior art.

[0009] In order to solve the above technical problems, the present invention discloses the following technical solutions:

[0010] In a first aspect, the present invention discloses a doxofylline tablet.

[0011] In some embodiments, the doxofylline tablets are made from the following raw materials in parts by weight:

[0012]

[0013] In some embodiments, the doxofylline tablets are made from the following raw materials in parts by weight:

[0014]

[0015] In some embodiments, the doxofylline tablets are made from the following raw materials in parts by weight:

[0016]

[0017]

[0018] In some embodiments, the weight proportion of the doxofylline is 35, 38, 40, 42 or 45. In some embodiments, the particle size D90 of the doxofylline is less than 250 μm, such as less than 230, 220, 210 or 200 μm; the D50 of the doxofylline is less than 100 μm, such as less than 90 or 80 μm.

[0019] In some embodiments, the filler is lactose, microcrystalline cellulose-sodium carboxymethyl cellulose, pregelatinized starch or a combination of any of the foregoing; in some embodiments, it is a mixture of lactose, microcrystalline cellulose-sodium carboxymethyl cellulose and pregelatinized starch, the lactose is lactose monohydrate, and the mass ratio of the lactose, microcrystalline cellulose-sodium carboxymethyl cellulose and pregelatinized starch is preferably 1.2-1.6:2.3-2.7:1, preferably 1.4:2.5:1. Among them, lactose has good compressibility. Microcrystalline cellulose-sodium carboxymethyl cellulose is a complex of microcrystalline cellulose and sodium carboxymethyl cellulose. In some embodiments, the mass content of microcrystalline cellulose in the complex is more than 80%; in some embodiments, the mass content of sodium carboxymethyl cellulose in the complex is 8.3%-17.3%; the complex has the characteristics of high thixotropy and low viscosity. The low viscosity of the excipient can effectively improve the disintegration and dissolution of the tablet, and its suspending effect can also improve the accumulation phenomenon after the drug disintegrates. Pregelatinized starch is a modified starch with self-lubricating effect. Compared with starch, pregelatinized starch can increase fluidity and compressibility.

[0020] In some embodiments, the glidant is silicon dioxide, colloidal silicon dioxide, talc or a combination of any of the foregoing; in some embodiments, it is a mixture of silicon dioxide, colloidal silicon dioxide and talc, and the mass ratio of silicon dioxide, colloidal silicon dioxide and talc is preferably 2.3-2.8:1:5.7-6.1, preferably 2.5-2.6:1:5.9; preferably, the talc is passed through a 20-100 mesh sieve, preferably a 40-80 mesh sieve, and preferably a 60 mesh sieve. Among them, silicon dioxide has a large specific surface area, good fluidity, has a large adsorption capacity for drugs, improves the hydrophilicity of the particles, can accelerate the disintegration of tablets, and disintegrates extremely finely, which is conducive to the absorption of drugs. The colloidal silicon dioxide has a very fine particle size, can pass through a 200 mesh sieve, and has an extremely low density. Its small particle size and large specific surface area give it good fluidity, improve particle fluidity and tablet sticking phenomenon. Talc fills the depressions on the surface of drug powders, thereby reducing the friction between drug powders and improving material fluidity.

[0021] In some embodiments, the binder is povidone and / or copovidone povidone; in some embodiments, it is a mixture of copovidones, and the mass ratio of povidone to copovidone is preferably 1.3-1.5: 1, preferably 1.4: 1. The binder provided by the present invention can improve the dissolution rate of doxofylline tablets in the later stage and improve the compressibility.

[0022] In some embodiments, the lubricant is magnesium stearate; the magnesium stearate is sieved through a 20-100 mesh sieve, preferably sieved through a 40-80 mesh sieve, preferably sieved through a 60 mesh sieve.

[0023] In some embodiments, the disintegrant is cross-linked sodium carboxymethylcellulose, which has a better water absorption and swelling capacity than low-substituted sodium carboxymethylcellulose and microcrystalline cellulose. It can disintegrate particles through capillary action and swelling action, promote drug release and dissolution, and also improve the problem of dissolution variability.

[0024] In some embodiments, the doxofylline tablets are prepared by a mixing method comprising: first mixing doxofylline, a filler, a binder, a disintegrant and a portion of a glidant in a wet granulator; adding the remaining glidant and lubricant, performing a second mixing in a wet granulator, tableting and packaging.

[0025] Wherein, part of the flow aid is silicon dioxide.

[0026] Wherein, the first mixing is obtained by shear mixing of a wet granulator; the stirring speed of the wet granulator is 60-160rpm, such as 100, 110, 120rpm; the cutting speed of the wet granulator is 400-800rpm, such as 500, 600, 700rpm; the mixing time is 400-800s, such as 500, 600, 700s.

[0027] Wherein, the second mixing is obtained by shear mixing of a wet granulator; the stirring speed of the wet granulator is 60-160rpm, such as 100, 110, 120rpm; the cutting speed of the wet granulator is 400-800rpm, such as 500, 600, 700rpm; the mixing time is 100-500s, such as 500, 600, 700s.

[0028] The tabletting pressure is 15-35KN, and the hardness is controlled at 4-10kg.

[0029] The coating is a polyvinyl chloride / polyvinylidene chloride solid medicinal composite hard tablet and a medicinal aluminum foil for inner packaging, and the secondary packaging is a polyester / aluminum / polyethylene medicinal composite film.

[0030] In some embodiments, the doxofylline tablets are made from the following raw materials in parts by weight:

[0031]

[0032] The particle size D90 of the doxofylline is less than 200 μm, and the D50 is less than 80 μm;

[0033] The filler is a mixture of lactose monohydrate, microcrystalline cellulose-sodium carboxymethyl cellulose, and pregelatinized starch in a mass ratio of 1.2-1.6:2.3-2.7:1;

[0034] The glidant is a mixture of silicon dioxide, colloidal silicon dioxide and talc in a mass ratio of 2.3-2.8:1:5.7-6.1; the talc is sieved through a 60-mesh sieve;

[0035] The adhesive is a mixture of polyvidone and copolyvidone in a mass ratio of 1.3-1.5:1;

[0036] The lubricant is magnesium stearate, which is sieved through a 60-mesh sieve;

[0037] The disintegrant is cross-linked carboxymethyl cellulose sodium;

[0038] The doxofylline tablets are prepared by a method comprising the following mixing:

[0039] Theophylline, filler, binder, disintegrant and part of glidant are sheared in a wet granulator for first mixing; the remaining glidant and lubricant are added, and the mixture is sheared in a wet granulator for second mixing; tableting and packaging;

[0040] In the first mixing, the stirring speed of the wet granulator is 100-120 rpm, the cutting speed is 500-700 rpm, and the mixing time is 500-700 s;

[0041] In the second mixing, the stirring speed of the wet granulator is 100-120 rpm, the cutting knife speed is 500-700 rpm, and the mixing time is 200-400 s.

[0042] In a second aspect, the present invention discloses a method for preparing the doxofylline tablets described in the first aspect.

[0043] The method comprises the steps of first mixing doxofylline, a filler, a binder, a disintegrant and a part of a glidant in a wet granulator; adding the remaining glidant and a lubricant, and secondly mixing, tabletting and packaging in the wet granulator.

[0044] Wherein, part of the flow aid is silicon dioxide.

[0045] Wherein, the first mixing is obtained by shear mixing of a wet granulator; the stirring speed of the wet granulator is 60-160rpm, such as 100, 110, 120rpm; the cutting speed of the wet granulator is 400-800rpm, such as 500, 600, 700rpm; the mixing time is 400-800s, such as 500, 600, 700s.

[0046] Wherein, the second mixing is obtained by shear mixing of a wet granulator; the stirring speed of the wet granulator is 60-160rpm, such as 100, 110, 120rpm; the cutting speed of the wet granulator is 400-800rpm, such as 500, 600, 700rpm; the mixing time is 100-500s, such as 500, 600, 700s.

[0047] The tabletting pressure is 15-35KN, and the hardness is controlled at 4-10kg.

[0048] The coating is a polyvinyl chloride / polyvinylidene chloride solid medicinal composite hard tablet and a medicinal aluminum foil for inner packaging, and the secondary packaging is a polyester / aluminum / polyethylene medicinal composite film.

[0049] Beneficial effects:

[0050] The invention provides a doxofylline tablet with simple preparation process, stable quality and good mixing uniformity and a preparation method thereof. The dissolution of the doxofylline tablet provided by the invention is similar to that of a reference preparation, and the content is uniform, the stability is good, and the tablet has good compressibility. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more clear.

[0052] Figure 1 It is the dissolution curve diagram of Example 1-3 and Comparative Example 1-4. DETAILED DESCRIPTION

[0053] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0054] The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials described are commercially available unless otherwise specified.

[0055] The materials used in the present invention are as follows: lactose (monohydrate) model: Tablettose 70, produced by: German Meijile Co., Ltd.; pregelatinized starch model: LYCATAB C, produced by: French Roquette Company; microcrystalline cellulose-sodium carboxymethyl cellulose model: RC-591, produced by: DuPont Nutrition USA Inc; povidone model: K30, produced by: BASF (China) Co., Ltd.; copovidone model: S-630, produced by: ISP Technologies Inc; cross-linked sodium carboxymethyl cellulose model: SD-711, produced by: DuPont Nutrition USA Inc; silicon dioxide manufacturer: Huzhou Zhanwang Pharmaceutical Co., Ltd.; colloidal silicon dioxide model: AEROSIL200Pharma, produced by: Evonik Operations GmbH; talc model: 88-45, produced by: Guangxi Longsheng Huamei Talc Development Co., Ltd.

[0056] Example 1

[0057] A method for preparing a stable doxofylline tablet comprises the following steps when producing 1000 tablets:

[0058] (1) Raw material crushing: The doxofylline raw material is crushed by a WFS-12H hammer mill. The particle size control range d(0.9) shall not exceed 200 μm, and d(0.5) shall not exceed 80 μm.

[0059] (2) Weighing and screening of raw and auxiliary materials: Weigh each raw material and auxiliary material according to the weight ratio.

[0060] 40 parts of doxofylline, 4.2 parts of lactose, 1.5 parts of silicon dioxide, 3 parts of pregelatinized starch, 3.5 parts of talc, 7.5 parts of microcrystalline cellulose-sodium carboxymethyl cellulose, 2 parts of povidone K30, 1.4 parts of copovidone, 0.3 parts of magnesium stearate, 0.6 parts of colloidal silicon dioxide, and 0.1 parts of cross-linked sodium carboxymethyl cellulose.

[0061] Among them, talc powder passed through a 1.5mm round hole sieve; magnesium stearate passed through a 60 mesh sieve.

[0062] (3) First step of mixing: the sieved mixture of doxofylline, lactose, pregelatinized starch, microcrystalline cellulose-sodium carboxymethyl cellulose, povidone K30, copovidone, croscarmellose sodium and silicon dioxide was added to a wet granulator for mixing. The stirring speed of the wet granulator was 110 rpm, the cutting speed was 600 rpm, and the mixing time was 600 s.

[0063] (4) Second step of mixing: Add sieved talc, colloidal silicon dioxide and magnesium stearate that has passed through a 60-mesh sieve into the first step of mixing. Continue mixing in the wet granulator at a stirring speed of 110 rpm, a cutting speed of 600 rpm, and a mixing time of 300 s. Obtain intermediate powder A. Take a sample to test the content of intermediate A.

[0064] (5) Tableting: The intermediate A obtained in step (4) is installed in a mold, and the tableting pressure is 15 KN. The tablet weight to be pressed is calculated according to the content result of the intermediate A, and the tablet weight difference is controlled within ±3%, and the hardness is 5 kg to 11 kg.

[0065] (6) Packaging: The inner packaging is made of polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard sheet and pharmaceutical aluminum foil, and the secondary packaging is polyester / aluminum / polyethylene pharmaceutical composite film.

[0066] Example 2

[0067] A method for preparing a stable doxofylline tablet comprises the following steps when producing 1000 tablets:

[0068] (1) Raw material crushing: The doxofylline raw material is crushed by a WFS-12H hammer mill. The particle size control range d(0.9) shall not exceed 200 μm, and d(0.5) shall not exceed 80 μm.

[0069] (2) Weighing and screening of raw and auxiliary materials: Weigh each raw material and auxiliary material according to the weight ratio.

[0070] 40 parts of doxofylline, 3.44 parts of lactose, 2.15 parts of silicon dioxide, 2.46 parts of pregelatinized starch, 5 parts of talc, 6.1 parts of microcrystalline cellulose-sodium carboxymethyl cellulose, 3.95 parts of povidone K30, 0.1 part of magnesium stearate, 0.85 part of colloidal silicon dioxide, and 0.05 part of cross-linked sodium carboxymethyl cellulose.

[0071] Among them, talc powder passed through a 1.5mm round hole sieve; magnesium stearate passed through a 60 mesh sieve.

[0072] (3) First step of mixing: the sieved mixture of doxofylline, lactose, pregelatinized starch, microcrystalline cellulose-sodium carboxymethyl cellulose, povidone K30, cross-linked sodium carboxymethyl cellulose and silicon dioxide was added to a wet granulator for mixing. The stirring speed of the wet granulator was 110 rpm, the cutting speed was 600 rpm, and the mixing time was 600 s.

[0073] (4) Second step of mixing: Add sieved talc, colloidal silicon dioxide and magnesium stearate that has passed through a 60-mesh sieve into the first step of mixing. Continue mixing in the wet granulator at a stirring speed of 110 rpm, a cutting speed of 600 rpm, and a mixing time of 300 s. Obtain intermediate powder A. Take a sample to test the content of intermediate A.

[0074] (5) Tableting: The intermediate A obtained in step (4) is installed in a mold, and the tableting pressure is 15 KN. The tablet weight to be pressed is calculated according to the content result of the intermediate A, and the tablet weight difference is controlled within ±3%, and the hardness is 5 kg to 11 kg.

[0075] (6) Packaging: The inner packaging is made of polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard sheet and pharmaceutical aluminum foil, and the secondary packaging is polyester / aluminum / polyethylene pharmaceutical composite film.

[0076] Example 3

[0077] A method for preparing a stable doxofylline tablet comprises the following steps when producing 1000 tablets:

[0078] (1) Raw material crushing: The doxofylline raw material is crushed by a WFS-12H hammer mill. The particle size control range d(0.9) shall not exceed 200 μm, and d(0.5) shall not exceed 80 μm.

[0079] (2) Weighing and screening of raw and auxiliary materials: Weigh each raw material and auxiliary material according to the weight ratio.

[0080] 40 parts of doxofylline, 5.22 parts of lactose, 1.1 parts of silicon dioxide, 3.66 parts of pregelatinized starch, 2.48 parts of talc, 9.12 parts of microcrystalline cellulose-sodium carboxymethyl cellulose, 1.4 parts of copovidone, 0.3 parts of magnesium stearate, 0.42 parts of colloidal silicon dioxide, and 0.4 parts of cross-linked sodium carboxymethyl cellulose.

[0081] Among them, talc powder passed through a 1.5mm round hole sieve; magnesium stearate passed through a 60 mesh sieve.

[0082] (3) First step of mixing: the sieved mixture of doxofylline, lactose, pregelatinized starch, microcrystalline cellulose-sodium carboxymethyl cellulose, copovidone, croscarmellose sodium and silicon dioxide was added to a wet granulator for mixing. The stirring speed of the wet granulator was 110 rpm, the cutting speed was 600 rpm, and the mixing time was 600 s.

[0083] (4) Second step of mixing: Add sieved talc, colloidal silicon dioxide and magnesium stearate that has passed through a 60-mesh sieve into the first step of mixing. Continue mixing in the wet granulator at a stirring speed of 110 rpm, a cutting speed of 600 rpm, and a mixing time of 300 s. Obtain intermediate powder A. Take a sample to test the content of intermediate A.

[0084] (5) Tableting: The intermediate A obtained in step (4) is installed in a mold, and the tableting pressure is 15 KN. The tablet weight to be pressed is calculated according to the content result of the intermediate A, and the tablet weight difference is controlled within ±3%, and the hardness is 5 kg to 11 kg.

[0085] (6) Packaging: The inner packaging is made of polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard sheet and pharmaceutical aluminum foil, and the secondary packaging is polyester / aluminum / polyethylene pharmaceutical composite film.

[0086] Comparative Example 1

[0087] The particle size of the doxofylline raw material after crushing is larger than that in Example 1. When producing 1000 tablets, the method comprises the following steps:

[0088] (1) Raw material crushing: The doxofylline raw material was crushed by a WFS-12H hammer mill, and the particle size control range was d(0.9) 250 to 350 μm, and d(0.5) was greater than 100 μm.

[0089] (2) Weighing and screening of raw and auxiliary materials: Weigh each raw material and auxiliary material according to the weight ratio.

[0090] 40 parts of doxofylline, 4.2 parts of lactose, 1.5 parts of silicon dioxide, 3 parts of pregelatinized starch, 3.5 parts of talc, 7.5 parts of microcrystalline cellulose-sodium carboxymethyl cellulose, 2 parts of povidone K30, 1.4 parts of copovidone, 0.3 parts of magnesium stearate, 0.6 parts of colloidal silicon dioxide, and 0.1 parts of cross-linked sodium carboxymethyl cellulose.

[0091] Among them, talc powder passed through a 1.5mm round hole sieve; magnesium stearate passed through a 60 mesh sieve.

[0092] (3) First step of mixing: the sieved mixture of doxofylline, lactose, pregelatinized starch, microcrystalline cellulose-sodium carboxymethyl cellulose, povidone K30, copovidone, croscarmellose sodium and silicon dioxide was added to a wet granulator for mixing. The stirring speed of the wet granulator was 110 rpm, the cutting speed was 600 rpm, and the mixing time was 600 s.

[0093] (4) Second step of mixing: Add sieved talc, colloidal silicon dioxide and magnesium stearate that has passed through a 60-mesh sieve into the first step of mixing. Continue mixing in the wet granulator at a stirring speed of 110 rpm, a cutting speed of 600 rpm, and a mixing time of 300 s. Obtain intermediate powder A. Take a sample to test the content of intermediate A.

[0094] (5) Tableting: The intermediate A obtained in step (4) is installed in a mold, and the tableting pressure is 15 KN. The tablet weight to be pressed is calculated according to the content result of the intermediate A, and the tablet weight difference is controlled within ±3%, and the hardness is 5 kg to 11 kg.

[0095] (6) Packaging: The inner packaging is made of polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard sheet and pharmaceutical aluminum foil, and the secondary packaging is polyester / aluminum / polyethylene pharmaceutical composite film.

[0096] Comparative Example 2

[0097] The cross-linked carboxymethyl cellulose sodium in the disintegrant of doxofylline tablets is replaced with low-substituted carboxymethyl cellulose sodium, and the production of 1000 tablets includes the following steps

[0098] (1) Raw material crushing: The doxofylline raw material is crushed by a WFS-12H hammer mill. The particle size control range d(0.9) shall not exceed 200 μm, and d(0.5) shall not exceed 80 μm.

[0099] (2) Weighing and screening of raw and auxiliary materials: Weigh each raw material and auxiliary material according to the weight ratio.

[0100] 40 parts of doxofylline, 4.2 parts of lactose, 1.5 parts of silicon dioxide, 3 parts of pregelatinized starch, 3.5 parts of talc, 7.5 parts of microcrystalline cellulose-sodium carboxymethyl cellulose, 2 parts of povidone K30, 1.4 parts of copovidone, 0.3 parts of magnesium stearate, 0.6 parts of colloidal silicon dioxide, and 0.1 parts of low-substituted sodium carboxymethyl cellulose.

[0101] Among them, talc powder passed through a 1.5mm round hole sieve; magnesium stearate passed through a 60 mesh sieve.

[0102] (3) First step of mixing: the sieved mixture of doxofylline, lactose, pregelatinized starch, microcrystalline cellulose-sodium carboxymethyl cellulose, povidone K30, copovidone, low-substituted sodium carboxymethyl cellulose and silicon dioxide was added to a wet granulator for mixing. The stirring speed of the wet granulator was 110 rpm, the cutting speed was 600 rpm, and the mixing time was 600 s.

[0103] (4) Second step of mixing: Add sieved talc, colloidal silicon dioxide and magnesium stearate that has passed through a 60-mesh sieve into the first step of mixing. Continue mixing in the wet granulator at a stirring speed of 110 rpm, a cutting speed of 600 rpm, and a mixing time of 300 s. Obtain intermediate powder A. Take a sample to test the content of intermediate A.

[0104] (5) Tableting: The intermediate A obtained in step (4) is installed in a mold, and the tableting pressure is 15 KN. The tablet weight to be pressed is calculated according to the content result of the intermediate A, and the tablet weight difference is controlled within ±3%, and the hardness is 5 kg to 11 kg.

[0105] (6) Packaging: The inner packaging is made of polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard sheet and pharmaceutical aluminum foil, and the secondary packaging is polyester / aluminum / polyethylene pharmaceutical composite film.

[0106] Comparative Example 3

[0107] The mixture of povidone and copovidone in the binder of doxofylline tablets is replaced with corn starch. When producing 1000 tablets, the following steps are included:

[0108] (1) Raw material crushing: The doxofylline raw material is crushed by a WFS-12H hammer mill. The particle size control range d(0.9) shall not exceed 200 μm, and d(0.5) shall not exceed 80 μm.

[0109] (2) Weighing and screening of raw and auxiliary materials: Weigh each raw material and auxiliary material according to the weight ratio.

[0110] 40 parts of doxofylline, 4.2 parts of lactose, 1.5 parts of silicon dioxide, 3 parts of pregelatinized starch, 3.5 parts of talc, 7.5 parts of microcrystalline cellulose-sodium carboxymethyl cellulose, 3.4 parts of corn starch, 0.3 parts of magnesium stearate, 0.6 parts of colloidal silicon dioxide, and 0.1 parts of cross-linked sodium carboxymethyl cellulose.

[0111] Among them, talc powder passed through a 1.5mm round hole sieve; magnesium stearate passed through a 60 mesh sieve.

[0112] (3) First step of mixing: the sieved mixture of doxofylline, lactose, pregelatinized starch, microcrystalline cellulose-sodium carboxymethyl cellulose, corn starch, cross-linked sodium carboxymethyl cellulose and silicon dioxide was added to a wet granulator for mixing. The stirring speed of the wet granulator was 110 rpm, the cutting speed was 600 rpm, and the mixing time was 600 s.

[0113] (4) Second step of mixing: Add sieved talc, colloidal silicon dioxide and magnesium stearate that has passed through a 60-mesh sieve into the first step of mixing. Continue mixing in the wet granulator at a stirring speed of 110 rpm, a cutting speed of 600 rpm, and a mixing time of 300 s. Obtain intermediate powder A. Take a sample to test the content of intermediate A.

[0114] (5) Tableting: The intermediate A obtained in step (4) is installed in a mold, and the tableting pressure is 15 KN. The tablet weight to be pressed is calculated according to the content result of the intermediate A, and the tablet weight difference is controlled within ±3%, and the hardness is 5 kg to 11 kg.

[0115] (6) Packaging: The inner packaging is made of polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard sheet and pharmaceutical aluminum foil, and the secondary packaging is polyester / aluminum / polyethylene pharmaceutical composite film.

[0116] Comparative Example 4

[0117] The preparation of doxofylline tablets is to change the wet granulation, cutting and mixing to a hopper mixer for mixing. When producing 1000 tablets, the following steps are included:

[0118] (1) Raw material crushing: The doxofylline raw material is crushed by a WFS-12H hammer mill. The particle size control range d(0.9) shall not exceed 200 μm, and d(0.5) shall not exceed 80 μm.

[0119] (2) Weighing and screening of raw and auxiliary materials: Weigh each raw material and auxiliary material according to the weight ratio.

[0120] 40 parts of doxofylline, 4.2 parts of lactose, 1.5 parts of silicon dioxide, 3 parts of pregelatinized starch, 3.5 parts of talc, 7.5 parts of microcrystalline cellulose-sodium carboxymethyl cellulose, 2 parts of povidone K30, 1.4 parts of copovidone, 0.3 parts of magnesium stearate, 0.6 parts of colloidal silicon dioxide, and 0.1 parts of cross-linked sodium carboxymethyl cellulose.

[0121] Among them, talc powder passed through a 1.5mm round hole sieve; magnesium stearate passed through a 60 mesh sieve.

[0122] (3) First step of mixing: the sieved mixture of doxofylline, lactose, pregelatinized starch, microcrystalline cellulose-sodium carboxymethyl cellulose, povidone K30, copovidone, croscarmellose sodium and silicon dioxide was added to a hopper mixer and mixed at a mixing speed of 19 rpm and a mixing time of 20 min.

[0123] (4) Second step: Add sieved talc, colloidal silicon dioxide and magnesium stearate that has passed through a 60-mesh sieve and mix in a hopper mixer. The mixing speed is 19 rpm and the mixing time is 10 min. Intermediate powder A is obtained. Samples are taken to detect the content of intermediate A.

[0124] (5) Tableting: The intermediate A obtained in step (4) is installed in a mold, and the tableting pressure is 15 KN. The tablet weight to be pressed is calculated according to the content result of the intermediate A, and the tablet weight difference is controlled within ±3%, and the hardness is 5 kg to 11 kg.

[0125] (6) Packaging: The inner packaging is made of polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard sheet and pharmaceutical aluminum foil, and the secondary packaging is polyester / aluminum / polyethylene pharmaceutical composite film.

[0126] Test 1

[0127] The dissolution curves of the reference preparation (ABC Farmaceutici SPA, the licensed manufacturer of doxofylline tablets), examples 1-3 and comparative examples 1-4 were measured, and the dissolution curves under the conditions of 900 mL of 0.1 mol / L hydrochloric acid medium and 50 rpm of the paddle method were selected as the basis for determination. The experimental results under 900 mL of the dissolution medium were measured at 37°C. Figure 1 As shown in Table 1, f2 is the similarity factor of the dissolution curves of each embodiment, comparative example and reference preparation. The similarity factors of the embodiments are all greater than 50, so the dissolution results of the embodiments are similar to those of the reference; comparative examples 1 and 2 dissolve slowly and have large dissolution variability, and comparative example 3 dissolves much faster than the reference, and the rapid disintegration in the first 5 minutes leads to too fast dissolution in the first 10 minutes.

[0128] Table 1

[0129]

[0130] Test 2

[0131] The products of the above examples were subjected to influencing factors (high temperature 60°C, light 4500±500lux / h, high temperature and high humidity 60°C+RH75%) for 10 days, accelerated stability test (40°C / RH75%) for 6 months, and properties, related substances, solubility (using 900ml of 0.1mol / L hydrochloric acid solution as dissolution medium, paddle method 100rpm, sampling after 30 minutes, Chinese Pharmacopoeia dissolution apparatus 2 at 37°C), and content comparison. The products obtained in Examples 1-3 have stable content, good solubility, and no impurity 1 (doxofylline impurity 1, C 10 H 16 N4O3), theophylline (C7H8N4O2) and other related substances with good stability.

[0132] Table 2

[0133]

[0134] Test 3

[0135] The bulk density of the intermediate powder A materials of Example 1, Example 2, Example 3 and Comparative Example 4 was tested, referring to the bulk density and tap density test method of 200 Chinese Pharmacopoeia 0993. The results are shown in Table 3. The materials of Examples 1-3 have good compressibility, while the powder compression index of Comparative Examples 1-4 is higher than that of Examples 1-3, and the compressibility is reduced. The material of Comparative Example 4 has poor compressibility. Compared with Comparative Example 3, the adhesive provided by the present invention can improve the compressibility. Compared with Comparative Example 4, the present invention uses a wet granulator for shear mixing to improve the bulk density of the mixed material, so that the total mixed material has better compressibility.

[0136] Table 3

[0137]

[0138] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A doxofylline tablet, characterized in that: Made from the following raw materials in parts by weight: The adhesive is povidone and / or copovidone; The disintegrant is cross-linked carboxymethyl cellulose sodium.

2. The doxofylline tablets according to claim 1, characterized in that: Made from the following raw materials in parts by weight: Preferably, it is made from the following raw materials in parts by weight:

3. The doxofylline tablets according to claim 1, characterized in that: The particle size D90 of the doxofylline is less than 250 μm, preferably less than 200 μm; the particle size D50 of the doxofylline is less than 100 μm, preferably less than 80 μm.

4. The doxofylline tablets according to claim 1, characterized in that: The filler is lactose, microcrystalline cellulose-sodium carboxymethyl cellulose, pregelatinized starch or a combination of any of the foregoing, preferably a mixture of lactose, microcrystalline cellulose-sodium carboxymethyl cellulose and pregelatinized starch, the lactose is preferably lactose monohydrate, and the mass ratio of lactose, microcrystalline cellulose-sodium carboxymethyl cellulose and pregelatinized starch is preferably 1.2-1.6:2.3-2.7:1, preferably 1.4:2.5:

1.

5. The doxofylline tablets according to claim 1, characterized in that: The glidant is silicon dioxide, colloidal silicon dioxide, talc or a combination of any of the foregoing, preferably a mixture of silicon dioxide, colloidal silicon dioxide and talc, and the mass ratio of silicon dioxide, colloidal silicon dioxide and talc is preferably 2.3-2.8:1:5.7-6.1, preferably 2.5-2.6:1:5.9; preferably, the talc is sieved through a 20-100 mesh sieve, preferably through a 40-80 mesh sieve, and preferably through a 60 mesh sieve.

6. The doxofylline tablets according to claim 1, characterized in that: The adhesive is a mixture of povidone and copovidone, and the mass ratio of povidone to copovidone is preferably 1.3-1.5:1, preferably 1.4:1; Preferably, the lubricant is magnesium stearate; preferably, the magnesium stearate is sieved through a 20-100 mesh sieve, preferably sieved through a 40-80 mesh sieve, preferably sieved through a 60 mesh sieve.

7. The doxofylline tablet according to any one of claims 1 to 6, characterized in that: The doxofylline tablets are prepared by a method comprising the following mixing: The doxofylline, filler, binder, disintegrant and part of glidant are first mixed in a wet granulator; The remaining glidant and lubricant were added and the mixture was mixed for the second time in a wet granulator.

8. The method for preparing the doxofylline tablets according to any one of claims 1 to 6, characterized in that: The mixing steps include: The doxofylline, filler, binder, disintegrant and part of glidant are first mixed in a wet granulator; The remaining glidant and lubricant were added and the mixture was mixed for the second time in a wet granulator.

9. The doxofylline tablet according to claim 7 or the method according to claim 8, characterized in that: The part of the glidant is silicon dioxide; The first mixing is obtained by shear mixing in a wet granulator; the stirring speed of the wet granulator is 60-160 rpm, preferably 110 rpm; the cutting speed of the wet granulator is 400-800 rpm, preferably 600 rpm; The mixing time is 400-800s, preferably 600s; The second mixing is obtained by shear mixing in a wet granulator; the stirring speed of the wet granulator is 60-160 rpm, preferably 110 rpm; the cutting speed of the wet granulator is 400-800 rpm, preferably 600 rpm; The mixing time is 100-500s, preferably 300s; Preferably, the method further comprises tableting and packaging; The hardness of the tablet is controlled at 4-10kg.

10. A doxofylline tablet, characterized in that: Made from the following raw materials in parts by weight: The particle size D90 of the doxofylline is less than 200 μm, and the D50 is less than 80 μm; The filler is a mixture of lactose monohydrate, microcrystalline cellulose-sodium carboxymethyl cellulose, and pregelatinized starch in a mass ratio of 1.2-1.6:2.3-2.7:1; The glidant is a mixture of silicon dioxide, colloidal silicon dioxide and talc in a mass ratio of 2.3-2.8:1:5.7-6.1; the talc is sieved through a 60-mesh sieve; The adhesive is a mixture of polyvidone and copolyvidone in a mass ratio of 1.3-1.5:1; The lubricant is magnesium stearate, which is sieved through a 60-mesh sieve; The disintegrant is cross-linked carboxymethyl cellulose sodium; The doxofylline tablets are prepared by a method comprising the following mixing: Theophylline, filler, binder, disintegrant and part of glidant are sheared in a wet granulator for first mixing; the remaining glidant and lubricant are added, and the mixture is sheared in a wet granulator for second mixing; tableting and packaging; In the first mixing, the stirring speed of the wet granulator is 100-120 rpm, the cutting speed is 500-700 rpm, and the mixing time is 500-700 s; In the second mixing, the stirring speed of the wet granulator is 100-120 rpm, the cutting knife speed is 500-700 rpm, and the mixing time is 200-400 s.

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