Doxofylline tablets and a process for the preparation thereof

Abstract

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

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical preparation, in particular to a doxofylline tablet and a preparation method thereof. BACKGROUND

[0002] This section provides background information only and can not necessarily be prior art.

[0003] Doxofylline is a derivative of methylxanthine, which is a bronchodilator that directly acts on bronchial relaxation of bronchial smooth muscle. The chemical name of doxofylline is 1, 3-dimethyl-7- (1, 3-dioxolyl-2-yl) methyl-3, 7-dihydro-1H-purine-2, 6-dione; the molecular formula is C 11 H 14 N4O4; the molecular weight is 266.26. Doxofylline can inhibit phosphodiesterase, and is suitable for bronchial asthma, asthmatic chronic bronchitis and other bronchospasm caused by dyspnea. It has the characteristics of strong effect, long acting time, fast distribution, low toxicity and small side effects. Doxofylline tablet is a new generation of theophylline derivative marketed in Italy in 1984, with the trade name ANSIMAR, and the license holder ABC Farmaceutici S.P.A.

[0004] Chinese patent application number CN105037361A discloses a doxofylline compound and a pharmaceutical composition thereof, wherein the tablet is prepared by mixing microcrystalline cellulose, sodium carboxymethyl cellulose, pregelatinized corn starch, lactose monohydrate with doxofylline, and then granulating with 6% povidone K30 ethanol solution as a binder, drying at 60°C for 5 hours, and then tabletting. The direct contact between lactose and doxofylline during the preparation of the soft material, and the high temperature and high humidity environment during the drying step make the preparation process prone to impurities. This leads to a decrease in dissolution rate during the stability process. Moreover, this disclosed patent requires drying for 5 hours, which is energy-consuming and time-consuming.

[0005] Chinese patent application number CN101028254B discloses a doxofylline sustained-release preparation and a preparation method thereof, wherein the fast-release part of the tablet is prepared by mixing lactose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and part of doxofylline with a lubricant to make a soft material, and then mixing. The doxofylline preparation disclosed in this patent has deficiencies in stability data, and impurities are generated during long-term storage, and the content of the active ingredient is reduced.

[0006] Chinese patent application number CN110898019A discloses a doxofylline tablet and a preparation method thereof, mixing silicon dioxide, mannitol, disintegrating agent, sodium carboxymethyl starch and talc powder to obtain a first mixture; mixing doxofylline and magnesium stearate to obtain a second mixture; mixing the first mixture and the second mixture to obtain a third mixture; and tabletting the third mixture. The disintegrating agent disclosed is microcrystalline cellulose, and the higher viscosity of the drug will cause accumulation after disintegration. This leads to large variability in dissolution.

[0007] Through research and analysis, it is found that the disclosed doxofylline tablet and preparation method thereof have deficiencies in stability, and the dissolution of commercially available doxofylline tablets is insufficient, with large variability. This is not conducive to the commercial production and clinical use of doxofylline tablets. It is necessary to develop a simple process for a stable doxofylline tablet and a preparation method thereof, with better stability and dissolution. SUMMARY

[0008] The technical problem to be solved by the present application is to provide a doxofylline tablet and a preparation method thereof to overcome the deficiencies of the prior art.

[0009] To solve the above technical problems, the present application discloses the following technical solutions:

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

[0011] In some embodiments, the doxofylline tablet is made from raw materials including the following weight fractions:

[0012]

[0013] In some embodiments, the doxofylline tablet is made from raw materials including the following weight fractions:

[0014]

[0015] In some embodiments, the doxofylline tablet is made from raw materials including the following weight fractions:

[0016]

[0017]

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

[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, a mixture of lactose, microcrystalline cellulose-sodium carboxymethyl cellulose, and pregelatinized starch, the lactose being monohydrate lactose, and the mass ratio of the lactose, microcrystalline cellulose-sodium carboxymethyl cellulose, and pregelatinized starch being 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, and 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, which has self-lubricating effect, and compared with starch, pregelatinized starch can increase the flowability and compressibility.

[0020] In some embodiments, the flow agent is silicon dioxide, colloidal silicon dioxide, talc, or a combination of any of the foregoing; in some embodiments, a mixture of silicon dioxide, colloidal silicon dioxide, and talc, the mass ratio of the silicon dioxide, colloidal silicon dioxide, and talc being 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, preferably a 60 mesh sieve. Among them, silicon dioxide has a large specific surface area, good flowability, and a large adsorption force on the drug, which can improve the hydrophilicity of the particles, accelerate the disintegration of the tablet, and disintegrate into very fine particles, which is conducive to the absorption of the drug. Colloidal silicon dioxide has a very fine particle size and can pass through a 200 mesh sieve, and has a very low density, and its small particle size and large specific surface area make it have good flowability, which can improve the flowability of the particles and the tablet sticking phenomenon. Talc can fill the depressions on the surface of the drug powder, thereby reducing the friction between the drug powders and improving the flowability of the materials.

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

[0022] In some embodiments, the lubricant is magnesium stearate; the magnesium stearate is passed through a 20-100 mesh sieve, preferably a 40-80 mesh sieve, preferably 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. The particles can be disintegrated by capillary action and swelling effect, which promotes the release and dissolution of the drug and also improves the dissolution variability problem.

[0024] In some embodiments, the theophylline tablet is made by a method comprising: mixing theophylline, filler, binder, disintegrant and part of the glidant in a wet granulator to obtain a first mixture; adding the rest of the glidant and lubricant in the wet granulator to obtain a second mixture; tabletting; and packaging.

[0025] In some embodiments, the part of the glidant is silicon dioxide.

[0026] In some embodiments, the first mixing is obtained by shearing mixing in a wet granulator; the stirring speed of the wet granulator is 60-160 rpm, such as 100, 110, 120 rpm; the cutter speed of the wet granulator is 400-800 rpm, such as 500, 600, 700 rpm; and the mixing time is 400-800 s, such as 500, 600, 700 s.

[0027] In some embodiments, the second mixing is obtained by shearing mixing in a wet granulator; the stirring speed of the wet granulator is 60-160 rpm, such as 100, 110, 120 rpm; the cutter speed of the wet granulator is 400-800 rpm, such as 500, 600, 700 rpm; and the mixing time is 100-500 s, such as 500, 600, 700 s.

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

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

[0030] In some embodiments, the theophylline tablet is made by a method comprising: mixing theophylline, filler, binder, disintegrant and part of the glidant in a wet granulator to obtain a first mixture; adding the rest of the glidant and lubricant in the wet granulator to obtain a second mixture; tabletting; and packaging.

[0031]

[0032] The particle size D90 of the theophylline is less than or equal to 200 μm, and the particle size D50 is less than or equal to 80 μm.

[0033] The filler is a mixture of lactose monohydrate, microcrystalline cellulose-sodium carboxymethylcellulose 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 with a mass ratio of 2.3-2.8:1:5.7-6.1; the talc is passed through a 60 mesh sieve;

[0035] The binder is a mixture of povidone and copovidone with a mass ratio of 1.3-1.5:1;

[0036] The lubricant is magnesium stearate, passed through a 60 mesh sieve;

[0037] The disintegrant is crosscarmellose sodium;

[0038] The doxofylline tablet is made by a method comprising mixing as follows:

[0039] Mixing doxofylline, a filler, a binder, a disintegrant and part of a glidant in a wet granulator by shearing to obtain a first mixture; adding the rest of the glidant and a lubricant in the wet granulator by shearing to obtain a second mixture; tabletting and packaging;

[0040] In the first mixing, the stirring speed of the wet granulator is 100-120 rpm, the cutter 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 cutter speed is 500-700 rpm, and the mixing time is 200-400 s.

[0042] In a second aspect, the application discloses a preparation method of the doxofylline tablet.

[0043] The method comprises mixing doxofylline, a filler, a binder, a disintegrant and part of a glidant in a wet granulator to obtain a first mixture; adding the rest of the glidant and a lubricant in the wet granulator to obtain a second mixture; tabletting and packaging.

[0044] The part of the glidant is silicon dioxide.

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

[0046] The second mixing is prepared by shearing mixing through a wet granulator; the stirring rotation speed of the wet granulator is 60-160 rpm, such as 100, 110, 120 rpm; the cutter rotation speed of the wet granulator is 400-800 rpm, such as 500, 600, 700 rpm; the mixing time is 100-500 s, such as 500, 600, 700 s.

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

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

[0049] Beneficial effects:

[0050] The present application provides a kind of preparation process simple, quality stable and good mixed uniformity doxofylline tablets and preparation method thereof.The dissolution of the doxofylline tablets provided by the present application is similar to that of the reference preparation, and the content is uniform, the stability is good, and the compressibility is also good. BRIEF DESCRIPTION OF DRAWINGS

[0051] The above and / or other aspects of the present application will become apparent and more readily appreciated from the following description, taken in conjunction with the accompanying drawings, in which:

[0052] Figure 1 The dissolution curves of Examples 1-3 and Comparative Examples 1-4 are shown in the following figures. DETAILED DESCRIPTION

[0053] The present application can be better understood according to the following examples. However, it will be readily apparent to those skilled in the art that the examples described are merely illustrative of the present application and should not be considered as limiting the scope of the application as described in the claims.

[0054] In the following examples, the experimental methods are conventional unless otherwise specified, and the reagents and materials are commercially available unless otherwise specified.

[0055] The materials used in the present application are as follows: lactose (monohydrate) with a model number of Tablettose 70 and a manufacturer of Merck KGaA, Germany; pre-gelatinized starch with a model number of LYCATAB C and a manufacturer of Roquette Freres, France; microcrystalline cellulose-sodium carboxymethyl cellulose with a model number of RC-591 and a manufacturer of DuPont Nutrition USA Inc; povidone with a model number of K30 and a manufacturer of BASF (China) Co., Ltd.; copovidone with a model number of S-630 and a manufacturer of ISP Technologies Inc; cross-linked sodium carboxymethyl cellulose with a model number of SD-711 and a manufacturer of DuPont Nutrition USA Inc; silicon dioxide with a manufacturer of Huzhou Zhanwang Pharmaceutical Co., Ltd.; colloidal silicon dioxide with a model number of AEROSIL 200 Pharma and a manufacturer of Evonik Operations GmbH; and talc with a model number of 88-45 and a manufacturer of Guangxi Longsheng Huamei Talc Development Co., Ltd.

[0056] Example 1

[0057] A preparation method of stable doxofylline tablets, when producing 1000 tablets, comprises the following steps:

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

[0059] (2) Raw material and auxiliary material weighing and sieving: each raw material and auxiliary material is weighed according to the weight ratio.

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

[0061] The talc is sieved through a 1.5 mm round hole sieve, and the magnesium stearate is sieved through a 60 mesh sieve.

[0062] (3) First step mixing: the mixture of sieved doxofylline, lactose, pre-gelatinized starch, microcrystalline cellulose-sodium carboxymethyl cellulose, povidone K30, copovidone, cross-linked sodium carboxymethyl cellulose, and silicon dioxide is added into a wet granulator for mixing. The stirring speed of the wet granulator is 110 rpm, the cutter speed is 600 rpm, and the mixing time is 600 s.

[0063] (4) Second mixing: add sieved talc, colloidal silicon dioxide and magnesium stearate sieved through 60 mesh into the first mixing. Continue mixing in the wet granulator with stirring speed of 110 rpm and cutter speed of 600 rpm for 300 s. Obtain intermediate powder A. Sample and test the content of intermediate A.

[0064] (5) Tabletting: install intermediate A obtained in step (4) into the die and tablet with a pressure of 15 KN. Calculate the weight of tablet to be pressed according to the content of intermediate A and control the weight difference within ±3% and the hardness within 5-11 kg.

[0065] (6) Packaging: inner package with PVC / PVDC solid pharmaceutical composite hard tablet and pharmaceutical aluminum foil and secondary package with polyester / aluminum / polyethylene pharmaceutical composite film.

[0066] Example 2

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

[0068] (1) Raw material crushing: crush doxofylline raw material with WFS-12H hammer crusher, control the particle size range d(0.9) to be less than 200 μm and d(0.5) to be less than 80 μm.

[0069] (2) Raw material and auxiliary material weighing and sieving: weigh each raw material and auxiliary material according to the weight ratio.

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

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

[0072] (3) First mixing: mix the mixture of sieved doxofylline, lactose, pregelatinized starch, microcrystalline cellulose-sodium carboxymethyl cellulose, povidone K30, cross-linked sodium carboxymethyl cellulose and silicon dioxide in the wet granulator. The stirring speed of the wet granulator is 110 rpm, the cutter speed is 600 rpm and the mixing time is 600 s.

[0073] (4) Second mixing: add sieved talc, colloidal silicon dioxide and magnesium stearate sieved through 60 mesh into the first mixing. Continue mixing in the wet granulator with stirring speed of 110 rpm and cutter speed of 600 rpm for 300 s. Obtain intermediate powder A. Sample and test the content of intermediate A.

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

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

[0076] Example 3

[0077] A preparation method of a stable doxofylline tablet, when producing 1000 tablets, comprises the following steps:

[0078] (1) raw material crushing: the doxofylline raw material is crushed by a WFS-12H hammer crusher, and the particle size control range d(0.9) is not more than 200 μm and d(0.5) is not more than 80 μm.

[0079] (2) raw material and auxiliary material weighing and sieving: each raw material and auxiliary material is weighed according to the weight ratio.

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

[0081] Among them, the talc is sieved through a 1.5 mm round hole sieve; and the magnesium stearate is sieved through a 60 mesh sieve.

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

[0083] (4) second step mixing: sieved talc, colloidal silicon dioxide and magnesium stearate sieved through a 60 mesh sieve are added into the first step mixing. The wet granulator continues to mix, the stirring speed is 110 rpm, the cutter speed is 600 rpm, and the mixing time is 300 s. Intermediate powder A is obtained. The content of intermediate A is detected by sampling.

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

[0085] (6) Packaging: inner package with polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard sheet and pharmaceutical aluminum foil, secondary package with polyester / aluminum / polyethylene pharmaceutical composite film.

[0086] Comparative Example 1

[0087] The particle size of the doxofylline bulk drug after crushing is larger than that of Example 1, and when 1000 tablets are produced, the following steps are included:

[0088] (1) Crushing of raw materials: the doxofylline bulk drug is crushed by WFS-12H hammer crusher, the particle size control range is d(0.9) 250 to 350 μm, d(0.5) is greater than 100 μm.

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

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

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

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

[0093] (4) Second step mixing: sieved talc, colloidal silicon dioxide and magnesium stearate sieved through a 60 mesh sieve are added into the first step mixing. The wet granulator continues to mix, the stirring speed is 110 rpm, the cutter speed is 600 rpm, and the mixing time is 300 s. Intermediate powder A is obtained. The content of intermediate A is detected by sampling.

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

[0095] (6) Packaging: inner package with polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard sheet and pharmaceutical aluminum foil, secondary package with 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. The production of 1000 tablets includes the following steps

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

[0099] (2) Weighing and screening of raw materials 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: 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 and mixed. The wet granulator was operated at a stirring speed of 110 rpm, a cutting speed of 600 rpm, and a mixing time of 600 s.

[0103] (4) Second Mixing Step: Add sieved talc, colloidal silicon dioxide, and magnesium stearate sieved through a 60-mesh sieve to the mixture in the first step. 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. This yields intermediate powder A. Samples are taken to determine the content of intermediate A.

[0104] (5) Tableting: Install the intermediate A obtained in step (4) in a mold and press the tablets at a pressure of 15 kN. Calculate the tablet weight based on the intermediate A content, controlling the tablet weight difference to within ±3% and the hardness to between 5 kg and 11 kg.

[0105] (6) Packaging: The inner packaging is made of polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard sheets 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. The production of 1000 tablets includes the following steps:

[0108] (1) Raw material crushing: The raw material of doxofylline is crushed by WFS-12H hammer crusher, the particle size control range d(0.9) should not be more than 200 μm, d(0.5) should not be more than 80 μm.

[0109] (2) Raw material and auxiliary material weighing and sieving: each raw material and auxiliary material is weighed according to the weight ratio.

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

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

[0112] (3) First step mixing: the mixture of doxofylline, lactose, pre-gelatinized starch, microcrystalline cellulose-sodium carboxymethyl cellulose, corn starch, cross-linked sodium carboxymethyl cellulose and silicon dioxide after sieving is added to the wet granulator for mixing. The stirring speed of the wet granulator is 110 rpm, the cutter speed is 600 rpm, and the mixing time is 600 s.

[0113] (4) Second step mixing: sieved talc, colloidal silicon dioxide and magnesium stearate sieved through a 60 mesh sieve are added to the first step mixing. The wet granulator continues to mix, the stirring speed is 110 rpm, the cutter speed is 600 rpm, and the mixing time is 300 s. The intermediate powder A is obtained. The content of the intermediate A is detected.

[0114] (5) Tabletting: the intermediate A obtained in step (4) is installed in the mold, and the tabletting pressure is 15 KN. The tablet weight difference is controlled within ±3%, and the hardness is 5 kg-11 kg according to the content of the intermediate A.

[0115] (6) Packaging: the inner packaging is carried out by using polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard tablet and pharmaceutical aluminum foil, and the secondary packaging is polyester / aluminum / polyethylene pharmaceutical composite film.

[0116] Comparative Example 4

[0117] When the wet granulation cutting mixing is changed to hopper mixer mixing during the preparation of doxofylline tablets, 1000 tablets are produced, including the following steps

[0118] (1) Raw material crushing: The raw material of doxofylline is crushed by WFS-12H hammer crusher, the particle size control range d(0.9) should not be more than 200 μm, d(0.5) should not be more than 80 μm.

[0119] (2) Raw materials and excipients are weighed and sieved: each raw material and excipient is weighed according to the weight ratio.

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

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

[0122] (3) First step mixing: the mixture of sieved doxofylline, lactose, pregelatinized starch, microcrystalline cellulose-sodium carboxymethylcellulose, povidone K30, copovidone, cross-linked sodium carboxymethylcellulose and silicon dioxide is added to the hopper mixer for mixing. The mixing speed is 19 rpm and the mixing time is 20 min.

[0123] (4) Second step mixing: sieved talc, colloidal silicon dioxide and sieved magnesium stearate are added to the hopper mixer for mixing. The mixing speed is 19 rpm and the mixing time is 10 min. Intermediate powder A is obtained. The content of intermediate A is detected by sampling.

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

[0125] (6) Packaging: inner packaging is performed with polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard tablets and pharmaceutical aluminum foil, and secondary packaging is performed with polyester / aluminum / polyethylene pharmaceutical composite film.

[0126] Test 1

[0127] By determining the dissolution curves of the reference preparation (Doxofylline tablets of the holder ABC Farmaceutici S.P.A.), the samples prepared in Examples 1-3 and Comparative Examples 1-4, and referring to the Chinese Pharmacopoeia standard and dissolution guidance principles, the dissolution curves under the conditions of 0.1 mol / L hydrochloric acid medium 900 mL and paddle method 50 rpm are selected as the basis for determination. The experimental results are measured at 37°C under 900 mL dissolution medium, as shown in Table 1 and Table 2. Figure 1 and Table 1. The f2 is the similarity factor of the dissolution curves of each example, comparative example and reference preparation, and the similarity factor of the example is greater than 50, so the dissolution results of the example are similar to the reference dissolution; the dissolution of Comparative Examples 1 and 2 is slow and has large variability, and the dissolution of Comparative Example 3 is much faster than the reference, and the rapid disintegration in the first 5 minutes leads to the rapid dissolution in the first 10 minutes.

[0128] Table 1

[0129]

[0130] Test 2

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

[0132] Table 2

[0133]

[0134] Test 3

[0135] The bulk density of the intermediate powder A material of Example 1, Example 2, Example 3, and Comparative Example 4 was detected, and the 200 Chinese Pharmacopoeia 0993 bulk density and tap density detection method was referred. The results are shown in Table 3, the material of Examples 1-3 is good in compressibility, the 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 is poor in compressibility. Compared with Comparative Example 3, the binder provided by the application can improve the compressibility. Compared with Comparative Example 4, the shear mixing in the wet granulator is selected in the application, the bulk density of the mixed material is improved, and the total mixed material has better compressibility.

[0136] Table 3

[0137]

[0138] The above-mentioned examples only express several embodiments of the application, and the description is more specific and detailed, but it cannot be understood as a limitation on the scope of the patent of the application. It should be noted that for ordinary skilled persons in the art, several modifications and improvements can be made without departing from the concept of the application, and these all belong to the protection scope of the application. Therefore, the protection scope of the patent of the application should be subject to the appended claims.

Claims

1. A doxofylline tablet, characterized in that Made from the following raw materials in parts by weight: 35-50 parts of doxofylline 10-20 parts filler 3-9 parts of glidant 1-4.35 parts adhesive 0.05-0.4 parts of lubricant 0.02-0.5 parts of disintegrant The particle size D90 of the doxofylline is less than 200 μm, and the D50 is less than 80 μm; the lubricant is sieved through a 20-100 mesh sieve; The filler is a mixture of lactose, 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 20-100 mesh sieve; The adhesive is povidone and / or copovidone; The lubricant is magnesium stearate; The disintegrant is cross-linked carboxymethyl cellulose sodium; Doxofylline, filler, binder, disintegrant and part of glidant are first mixed in a wet granulator; Add the remaining glidant and lubricant, and perform a second mixing in a wet granulator; tableting and packaging; 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; the cutter speed of the wet granulator is 400-800 rpm; and the mixing time is 400-800 s; The second mixing is obtained by shear mixing in a wet granulator; the stirring speed of the wet granulator is 60-160 rpm; the cutter speed of the wet granulator is 400-800 rpm; and the mixing time is 100-500 s.

2. The doxofylline tablets according to claim 1, wherein Made from the following raw materials in parts by weight: 35-45 parts of doxofylline 12-18 parts filler 4-8 parts of flow aid 1.4-3.95 parts of adhesive 0.1-0.3 parts of lubricant Disintegrant 0.05-0.4 parts.

3. The doxofylline tablets according to claim 1, characterized in that Made from the following raw materials in parts by weight: 35-45 parts of doxofylline Filler 13.7-15.7 parts 4.6-6.6 parts of glidant 2.4-4.4 parts adhesive 0.2-0.4 parts of lubricant Disintegrant 0.05-0.15 parts.

4. The doxofylline tablets according to claim 1, characterized in that The lactose is lactose monohydrate.

5. The doxofylline tablet according to claim 1, characterized in that The mass ratio of the lactose, microcrystalline cellulose-sodium carboxymethyl cellulose and pregelatinized starch is 1.4:2.5:

1.

6. The doxofylline tablets according to claim 1, characterized in that The mass ratio of the silicon dioxide, colloidal silicon dioxide and talc is 2.5-2.6:1:5.

9.

7. The doxofylline tablets according to claim 1, characterized in that The adhesive is a mixture of povidone and copovidone.

8. The doxofylline tablets according to claim 7, characterized in that The mass ratio of the polyvidone to the copolyvidone is 1.3-1.5:

1.

9. The doxofylline tablets according to claim 7, characterized in that The mass ratio of the povidone to the copovidone is 1.4:

1.

10. The doxofylline tablets according to claim 1, characterized in that The lubricant is passed through a 40-80 mesh sieve.

11. The doxofylline tablet according to claim 1, characterized in that The lubricant was passed through a 60-mesh sieve.

12. The method for preparing the doxofylline tablets according to any one of claims 1 to 11, characterized in that: The steps include: Doxofylline, a filler, a binder, a disintegrant, and a portion of a glidant are mixed in a wet granulator for a first time; the remaining glidant and lubricant are added, and a second mixing is performed in a wet granulator; Tableting and packaging; 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; the cutter speed of the wet granulator is 400-800 rpm; and the mixing time is 400-800 s; The second mixing is obtained by shear mixing in a wet granulator; the stirring speed of the wet granulator is 60-160 rpm; the cutter speed of the wet granulator is 400-800 rpm; and the mixing time is 100-500 s.

13. The doxofylline tablet according to claim 1 or the method according to claim 12, characterized in that: The hardness of the tablet is controlled at 4-10kg.

14. The doxofylline tablet according to claim 1 or the method according to claim 12, characterized in that: In the first mixing, the stirring speed of the wet granulator is 110 rpm, the cutter speed is 600 rpm, and the mixing time is 400-800 s.

15. The doxofylline tablet according to claim 1 or the method according to claim 12, characterized in that: In the second mixing, the stirring speed of the wet granulator is 110 rpm, the cutter speed is 600 rpm, and the mixing time is 300 s.

16. A doxofylline tablet, characterized in that: Made from the following raw materials in parts by weight: 38-42 parts of doxofylline Filler 13.7-15.7 parts 4.6-6.6 parts of glidant 2.4-4.4 parts adhesive 0.2-0.4 parts of lubricant 0.05-0.15 parts of disintegrant 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 povidone and copovidone 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: Doxofylline, filler, binder, disintegrant and part of glidant are sheared in a wet granulator for first mixing; the remaining glidant and lubricant are added and sheared in a wet granulator for second mixing; tableting and packaging; The part of the glidant is silicon dioxide; In the first mixing, the stirring speed of the wet granulator is 100-120 rpm, the cutter 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 speed is 500-700 rpm, and the mixing time is 200-400 s.

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