Pharmaceutical composition containing purified micronized flavone component and preparation method thereof

Abstract

The invention discloses a pharmaceutical composition containing purified micronized flavone components and a preparation method of the pharmaceutical composition, and belongs to the technical field of pharmaceutical preparations. The pharmaceutical composition consists of purified micronized flavone components, an adhesive, a filling agent, a disintegrating agent, a lubricating agent and purified water, wherein the adhesive is gelatin, the jelly strength value of the gelatin is 100-200 Boomg, and the concentration of the gelatin aqueous solution is 10-15%. According to the preparation method, a hot-melting wet-process mixing granulator is adopted, so that the liquid state after gelatin is added can be effectively kept, materials are fully wetted, then the loosening degree of granules is controlled according to granulation parameters and granulation time, on the basis, purified micronized flavone components are wetted with ethyl alcohol, then the granules and gelatin are independently granulated, and the granules are prepared. And finally, mixing and tabletting with other auxiliary materials, so that the problems of wall sticking, uncoated tablets and the like in a wet granulation process can be effectively improved.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a pharmaceutical composition containing purified micronized flavonoid components and a preparation method thereof. Background Art

[0002] Purified micronized flavonoids are the main ingredients of Citrus Flavonoid Tablets, which were developed by Servier, France, and first launched in France in 1987 and entered the domestic market in 2001. It is mainly used to treat venous lymphatic insufficiency and acute hemorrhoidal attacks and other related diseases. It is recommended as a first-line / A level in the guidelines of many countries and has been widely recognized by clinicians and patients.

[0003] The main components of the purified micronized flavonoids are 90% diosmin and 10% other active flavonoid compounds, which are further prepared into oral tablets through a formulation process. Since the drug has low water solubility and can hardly be absorbed from the gastrointestinal tract, it mainly relies on enzyme hydrolysis in the intestine for absorption. Therefore, micronization technology is used in production to increase absorption and improve bioavailability. However, the raw materials often tend to aggregate easily after being crushed, have poor fluidity, and block the feeder during tableting.

[0004] Patent CN104906058A discloses a method for preparing diosmin tablets and a process thereof, wherein diosmin tablets are obtained by directly compressing diosmin with materials such as diethylene glycol monoethyl ether and an anti-adherent (kaolin) after mixing, so as to solve the problems that diosmin after micronization is easy to aggregate, the mixing uniformity is poor, and the dissolution effect becomes poor due to the increase in the particle size of the raw materials after wet granulation. However, diethylene glycol monoethyl ether and kaolin are unconventional excipients, and there are few manufacturers. In addition, ethylene glycol monoethyl ether has poor safety, so the prescription has certain risks.

[0005] Patent CN 115624520A discloses a diosmin-related cream, which indicates that oral solid preparations will increase the difficulty of medication for people with dysphagia and psychological difficulty in taking medicine. However, the purified micronized flavonoid components are mainly absorbed after enzymatic hydrolysis in the intestine, so the tablet dosage form of this product has certain advantages in pharmacokinetics.

[0006] Patent CN 117205200A discloses a method for preparing a citrus flavonoid composition, wherein the disintegrants are type A sodium carboxymethyl starch and type C sodium carboxymethyl starch, and the disintegrants are wet granulated with citrus flavonoids, fillers, glidants, adhesives and lubricants at a mass ratio of 10-30:5, which can solve the wall sticking phenomenon during the mixing process and avoid the risk of gelatin aqueous solution being easy to solidify during the granulation process as an adhesive. However, when gelatin is used as a wet granulation adhesive, it needs to be fully swollen and stirred at a certain temperature before it has an adhesive effect, and the obtained particles may have different degrees of looseness due to uneven dispersion of gelatin, resulting in flowery tablets during tableting. In addition, due to the high proportion of raw materials in this product, the addition of different types of disintegrants may lead to uneven mixing of auxiliary materials, which is difficult to detect, and there are differences in disintegration between tablets.

[0007] Therefore, it is necessary to develop a method for preparing a pharmaceutical composition containing purified micronized flavonoid components to solve the problems of stickiness of the purified micronized flavonoid components during wet granulation, easy coagulation and uneven dispersion of the gelatin aqueous solution resulting in different looseness of particles, and flowery tablets. Summary of the invention

[0008] In view of the above problems existing in the prior art, the technical problem to be solved by the present invention is to provide a pharmaceutical composition containing purified micronized flavonoid components, and the quality of the prepared pharmaceutical composition is stable. Another technical problem to be solved by the present invention is to provide a method for preparing the above pharmaceutical composition containing purified micronized flavonoid components, the preparation process is simple and controllable, the repeatability is strong, and it is easy to realize industrial production.

[0009] In order to solve the above technical problems, the technical solution adopted by the present invention is as follows:

[0010] A method for preparing a pharmaceutical composition containing purified micronized flavonoid components comprises the following steps: placing a gelatin aqueous solution and the moistened purified micronized flavonoid components in a hot melt wet granulator for granulation, controlling the looseness of the particles by controlling the granulation parameters and the granulation time, and then mixing with auxiliary materials for tableting and coating to prepare the pharmaceutical composition containing the purified micronized flavonoid components; wherein the gelatin has a jelly strength value of 100 to 200 BLoomg, the concentration of the gelatin aqueous solution is 10 to 15%, and the mass ratio of the purified micronized flavonoid components to the gelatin is 100:2.5 to 10.

[0011] Preferably, the temperature of the hot melt wet granulator is controlled at 40-70° C., the stirring speed is 120-200 rpm, the shearing speed is 1000-2000 rpm, and the granulation time is 5 min.

[0012] Preferably, the temperature of the hot melt wet granulator is controlled to be 40° C., the stirring speed is 180 rpm, the shearing speed is 1600 rpm, and the granulation time is 5 min.

[0013] The method for preparing the pharmaceutical composition containing the purified micronized flavonoid component specifically comprises the following steps:

[0014] 1) Wetting the purified micronized flavonoid component with ethanol;

[0015] 2) granulating the moistened purified micronized flavonoid component with gelatin;

[0016] 3) subjecting the granules obtained by granulation to wet granulation, drying and dry granulation;

[0017] 4) mixing a filler, a disintegrant and a lubricant with the dry granulated granules to obtain a total mixed granule;

[0018] 5) The total mixed granules are tableted and coated to prepare a pharmaceutical composition containing purified micronized flavonoid components.

[0019] Preferably, in step 1), the volume fraction of ethanol is 50% to 100%, and the mass ratio of ethanol to the purified micronized flavonoid component is 10 to 20:100.

[0020] More preferably, in step 1), the volume fraction of ethanol is 75% to 100%, and the mass ratio of ethanol to the purified micronized flavonoid component is 15:100.

[0021] Preferably, in step 5), a special-shaped punch is used to compress the total mixed particles into tablets, the tablet weight difference is within ±4%, and the hardness is 10-15 kgf; a coating solution is prepared according to a solid content of 12%; the main engine speed is controlled to be 12 rpm, the fan speed to be 1500 rpm, the atomization pressure to be 0.2 MPa, the inlet air temperature to be 65°C, the pump speed to be 1.5-2.5 rpm, the coating weight gain to be 2-3%, and the coating is carried out, and drying is continued for 30 minutes after the coating is completed.

[0022] The method for preparing a pharmaceutical composition containing purified micronized flavonoid components described in any one of the above items can prepare a pharmaceutical composition containing purified micronized flavonoid components.

[0023] Preferably, the pharmaceutical composition consists of purified micronized flavonoid component, a binder, a filler, a disintegrant, a lubricant and purified water.

[0024] Preferably, the binder is gelatin; the gelatin has a freezing force value of 100-200 BLoomg, the concentration of the gelatin aqueous solution is 10-15%, and the mass ratio of the purified micronized flavonoid component to the gelatin is 100:2.5-10. More preferably, the gelatin has a freezing force value of 120-150 BLoomg, the concentration of the gelatin aqueous solution is 12-15%, and the mass ratio of the purified micronized flavonoid component to the gelatin is 100:5-8.

[0025] The filler is selected from one or more of microcrystalline cellulose, silicified microcrystalline cellulose, and mannitol; the mass ratio of the purified micronized flavonoid component to the filler is 5 to 10: 1. More preferably, the mass ratio of the purified micronized flavonoid component to the filler is 8: 1.

[0026] The disintegrant is selected from one or more of cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose; the mass ratio of the purified micronized flavonoid component to the disintegrant is 15 to 26: 1. More preferably, the mass ratio of the purified micronized flavonoid component to the disintegrant is 19.8: 1.

[0027] The lubricant is selected from one or more of magnesium stearate, talc, colloidal silicon dioxide, and sodium stearyl fumarate. The mass ratio of the purified micronized flavonoid component to the lubricant is 80 to 38:1. More preferably, the mass ratio of the purified micronized flavonoid component to the lubricant is 49:1.

[0028] The application of the pharmaceutical composition containing the purified micronized flavonoid component in the preparation of medicines for treating venous lymphatic insufficiency and acute hemorrhoids.

[0029] Preferably, the pharmaceutical composition is a tablet.

[0030] The inventors have found through a large number of process equipment research and experimental investigations that the use of a hot melt wet mixing granulator can effectively maintain the liquid state of gelatin after addition, fully wet the material, and control the looseness of the particles through granulation parameters and granulation time. On this basis, the purified micronized flavonoid component is wetted with ethanol, granulated with gelatin separately, and then mixed with other auxiliary materials for tableting, which can effectively improve the problems of sticking and plain tablets in the wet granulation process.

[0031] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0032] (1) The present invention purifies the micronized flavonoid components by wetting with ethanol, which can effectively solve the electrostatic effects such as wall sticking and agglomeration caused by the excessively small particle size of the micronized raw materials;

[0033] (2) The present invention granulates the purified micronized flavonoid component alone, and can further improve the fluidity of the micronized raw material by adding an external filler, which is beneficial to reducing problems such as tablet weight differences caused by fluidity during industrial production;

[0034] (3) The present invention adopts a hot melt wet granulator for wet granulation. By controlling the equipment parameters, the liquid state of gelatin after addition can be effectively maintained, the risk of gelatin aqueous solution being easily solidified during the granulation process can be eliminated, and the material can be fully moistened. The plain tablets can be prevented from being flowery;

[0035] (4) The gelatin solution prepared by the present invention using gelatin with a freezing force value of 100-200 BLoomg has moderate viscosity and can fully wet the micronized raw materials without affecting the dissolution of the product and avoiding the phenomenon of plain tablets with flowery flakes;

[0036] (5) The pharmaceutical composition containing purified micronized flavonoid components prepared by the present invention does not slow down the dissolution of the product, and its dissolution behavior is comparable to that of the reference preparation, thus solving the problem that the particle size of the raw material becomes larger after wet granulation, resulting in poor dissolution effect, and the like in the prior art;

[0037] (6) The preparation process of the present invention is simple and controllable, with strong repeatability. It can solve the problems of sticking to the wall, easy coagulation and uneven dispersion of gelatin aqueous solution, and uneven particle size of plain tablets caused by the purified micronized flavonoid components after micronization during wet granulation. It is easy to realize industrial production and the quality of the products obtained is stable. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 It is a comparison chart of the cumulative dissolution curves of Example 1, Comparative Examples 1-4 and the reference preparation;

[0039] Figure 2 These are actual photos of the plain tablets prepared in Example 1 and Comparative Example 1. DETAILED DESCRIPTION

[0040] The present invention will be further illustrated below in conjunction with specific examples. The examples are implemented under the premise of the technical solution of the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. If specific conditions are not specified in the examples, they are carried out according to normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0041] The hot melt wet granulator used in the following examples is model MG6, and the wet granulator is model G6; the purified micronized flavonoid component selected is a microparticle mixture of 90% diosmin and 10% hesperidin; and the carboxymethyl starch used is the commonly used model C.

[0042] Example 1

[0043] 1. Recipe:

[0044]

[0045] 2. Preparation process:

[0046] (1) Material pretreatment: Place the purified micronized flavonoid component in a hot melt wet granulator, start stirring and shearing, control the stirring speed to 180 rpm, the shearing speed to 800 rpm, the temperature of the hot melt wet granulator to 40° C., and add ethanol to wet the purified micronized flavonoid component;

[0047] (2) Preparation of adhesive: using gelatin with a freezing strength of 120 BLoomg, prepare a gelatin aqueous solution with purified water at a concentration of 15%;

[0048] (3) Granulation: Spray a 15% gelatin aqueous solution into a hot melt wet granulator containing the moistened purified micronized flavonoid component. Control the temperature of the hot melt wet granulator at 40° C., the stirring speed at 180 rpm, and the shear speed at 1600 rpm to granulate the moistened purified micronized flavonoid component. The granulation is completed after running for 5 min.

[0049] (4) Wet granulation: The granules obtained in step 3) are wet granulated by a swing granulator (24 mesh screen);

[0050] (5) Drying: Place the wet granulated granules in an oven at 60°C and dry them until the moisture content is 3-4%. Then stop drying.

[0051] (6) Dry granulation: the dried granules are sieved through a 24-mesh screen;

[0052] (7) Total mixing: Add the dry whole granules and excipients (microcrystalline cellulose, sodium carboxymethyl starch, talc, and magnesium stearate) into a mixer and mix at 10 rpm for 10 min to ensure uniform mixing of the materials;

[0053] (8) Tabletting: Tableting is performed using a 16.5*8.3 mm special-shaped punch, with the tablet weight controlled to be 650 mg, the tablet weight variation within ±4%, and the hardness to be 10-15 kgf;

[0054] (9) Coating: Prepare coating solution according to solid content of 12%; control the main engine speed to 12 rpm, fan speed to 1500 rpm, atomization pressure to 0.2 MPa, air inlet temperature to 65°C, pump speed to 1.5-2.5 rpm, coating weight gain to 2-3%, and continue to dry in the pot for 30 min after coating.

[0055] Example 2

[0056] 1. Recipe:

[0057]

[0058] 2. Preparation process:

[0059] (1) Material pretreatment: Place the purified micronized flavonoid component in a hot melt wet granulator, start stirring and shearing, control the stirring speed to 180 rpm, the shearing speed to 800 rpm, the temperature of the hot melt wet granulator to 40° C., and add ethanol to wet the purified micronized flavonoid component;

[0060] (2) Preparation of adhesive: using gelatin with a freezing strength of 120 BLoomg, prepare a gelatin aqueous solution with purified water at a concentration of 12%;

[0061] (3) Granulation: Place a 12% gelatin aqueous solution and the moistened purified micronized flavonoid component in a hot melt wet granulator, control the temperature of the hot melt wet granulator to 40° C., the stirring speed to 180 rpm, and the shear speed to 1600 rpm, and granulate the moistened purified micronized flavonoid component for 5 min;

[0062] (4) Wet granulation: The granules obtained in step 3) are wet granulated by a swing granulator (24 mesh screen);

[0063] (5) Drying: Place the wet granulated granules in an oven at 60°C and dry them until the moisture content is 3-4%. Then stop drying.

[0064] (6) Dry granulation: the dried granules are sieved through a 24-mesh screen;

[0065] (7) Total mixing: Add the dry whole granules and excipients (microcrystalline cellulose, sodium carboxymethyl starch, talc, and magnesium stearate) into a mixer and mix at 10 rpm for 10 min to ensure uniform mixing of the materials;

[0066] (8) Tabletting: Tableting is performed using a 16.5*8.3 mm special-shaped punch, with the tablet weight controlled to be 650 mg, the tablet weight variation within ±4%, and the hardness to be 10-15 kgf;

[0067] (9) Coating: Prepare coating solution according to solid content of 12%, control main machine speed at 12 rpm, fan speed at 1500 rpm, atomization pressure at 0.2 MPa, air inlet temperature at 65°C, pump speed at 1.5-2.5 rpm, coating weight gain at 2-3%, and continue drying in the pot for 30 min after coating.

[0068] Example 3

[0069] 1. Formulation

[0070]

[0071] 2. Preparation process:

[0072] (1) Material pretreatment: Place the purified micronized flavonoid component in a hot melt wet granulator, start stirring and shearing, control the stirring speed to 180 rpm, the shearing speed to 800 rpm, the temperature of the hot melt wet granulator to 40° C., and add ethanol to wet the purified micronized flavonoid component;

[0073] (2) Preparation of adhesive: using 150 BLoomg gelatin with a freezing strength, prepare a gelatin aqueous solution with purified water at a concentration of 15%;

[0074] (3) Granulation: Place a 15% gelatin aqueous solution and the moistened purified micronized flavonoid component in a hot melt wet granulator, control the temperature of the hot melt wet granulator to 40° C., the stirring speed to 180 rpm, and the shear speed to 1600 rpm, and granulate the moistened purified micronized flavonoid component for 5 min;

[0075] (4) Wet granulation: The granules obtained in step 3) are wet granulated by a swing granulator (24 mesh screen);

[0076] (5) Drying: Place the wet granulated granules in an oven at 60°C and dry them until the moisture content is 3-4%. Then stop drying.

[0077] (6) Dry granulation: the dried granules are sieved through a 24-mesh screen;

[0078] (7) Total mixing: Add the dry whole granules and excipients (microcrystalline cellulose, sodium carboxymethyl starch, talc, and magnesium stearate) into a mixer and mix at 10 rpm for 10 min to ensure uniform mixing of the materials;

[0079] (8) Tabletting: Tableting is performed using a 16.5*8.3 mm special-shaped punch, with the tablet weight controlled to be 650 mg, the tablet weight variation within ±4%, and the hardness to be 10-15 kgf;

[0080] (9) Coating: Prepare coating solution according to solid content of 12%, control main machine speed at 12 rpm, fan speed at 1500 rpm, atomization pressure at 0.2 MPa, air inlet temperature at 65°C, pump speed at 1.5-2.5 rpm, coating weight gain at 2-3%, and continue drying in the pot for 30 min after coating.

[0081] Example 4

[0082] 1. Formulation

[0083]

[0084] 2. Preparation process:

[0085] (1) Material pretreatment: Place the purified micronized flavonoid component in a hot melt wet granulator, start stirring and shearing, control the stirring speed to 180 rpm, the shearing speed to 800 rpm, the temperature of the hot melt wet granulator to 60° C., and add ethanol to wet the purified micronized flavonoid component;

[0086] (2) Preparation of adhesive: using gelatin with a freezing strength of 120 BLoomg, prepare a gelatin aqueous solution with purified water at a concentration of 15%;

[0087] (3) Granulation: Place a 15% gelatin aqueous solution and the moistened purified micronized flavonoid component in a hot melt wet granulator, control the temperature of the hot melt wet granulator to 60° C., the stirring speed to 180 rpm, and the shear speed to 1600 rpm, and granulate the moistened purified micronized flavonoid component for 5 min;

[0088] (4) Wet granulation: The granules obtained in step 3) are wet granulated by a swing granulator (24 mesh screen);

[0089] (5) Drying: Place the wet granulated granules in an oven at 60°C and dry them until the moisture content is 3-4%. Then stop drying.

[0090] (6) Dry granulation: the dried granules are sieved through a 24-mesh screen;

[0091] (7) Total mixing: Add the dry whole granules and excipients (microcrystalline cellulose, sodium carboxymethyl starch, talc, and magnesium stearate) into a mixer and mix at 10 rpm for 10 min to ensure uniform mixing of the materials;

[0092] (8) Tabletting: Tableting is performed using a 16.5*8.3 mm special-shaped punch, with the tablet weight controlled to be 650 mg, the tablet weight variation within ±4%, and the hardness to be 10-15 kgf;

[0093] (9) Coating: Prepare coating solution according to solid content of 12%, control main machine speed at 12 rpm, fan speed at 1500 rpm, atomization pressure at 0.2 MPa, air inlet temperature at 65°C, pump speed at 1.5-2.5 rpm, coating weight gain at 2-3%, and continue drying in the pot for 30 min after coating.

[0094] Example 5

[0095] 1. Formulation

[0096]

[0097]

[0098] 2. Preparation process:

[0099] (1) Material pretreatment: Place the purified micronized flavonoid component in a hot melt wet granulator, start stirring and shearing, control the stirring speed to 180 rpm, the shearing speed to 800 rpm, the temperature of the hot melt wet granulator to 40° C., and add ethanol to wet the purified micronized flavonoid component;

[0100] (2) Preparation of adhesive: using gelatin with a freezing strength of 120 BLoomg, prepare a gelatin aqueous solution with purified water at a concentration of 15%;

[0101] (3) Granulation: Place a 15% gelatin aqueous solution and the moistened purified micronized flavonoid component in a hot melt wet granulator, control the temperature of the hot melt wet granulator to 40° C., the stirring speed to 200 rpm, and the shear speed to 1600 rpm, and granulate the moistened purified micronized flavonoid component for 5 min;

[0102] (4) Wet granulation: The granules obtained in step 3) are wet granulated by a swing granulator (24 mesh screen);

[0103] (5) Drying: Place the wet granulated granules in an oven at 60°C and dry them until the moisture content is 3-4%. Then stop drying.

[0104] (6) Dry granulation: the dried granules are sieved through a 24-mesh screen;

[0105] (7) Total mixing: Add the dry whole granules and excipients (microcrystalline cellulose, sodium carboxymethyl starch, talc, and magnesium stearate) into a mixer and mix at 10 rpm for 10 min to ensure uniform mixing of the materials;

[0106] (8) Tabletting: Tableting is performed using a 16.5*8.3 mm special-shaped punch, with the tablet weight controlled to be 650 mg, the tablet weight variation within ±4%, and the hardness to be 10-15 kgf;

[0107] (9) Coating: Prepare coating solution according to solid content of 12%, control main machine speed at 12 rpm, fan speed at 1500 rpm, atomization pressure at 0.2 MPa, air inlet temperature at 65°C, pump speed at 1.5-2.5 rpm, coating weight gain at 2-3%, and continue drying in the pot for 30 min after coating.

[0108] Example 6

[0109] 1. Formulation

[0110]

[0111]

[0112] 2. Preparation process:

[0113] (1) Material pretreatment: Place the purified micronized flavonoid component in a hot melt wet granulator, start stirring and shearing, control the stirring speed to 180 rpm, the shearing speed to 800 rpm, the temperature of the hot melt wet granulator to 40° C., and add ethanol to wet the purified micronized flavonoid component;

[0114] (2) Preparation of adhesive: using gelatin with a freezing strength of 120 BLoomg, prepare a gelatin aqueous solution with purified water at a concentration of 15%;

[0115] (3) Granulation: Place a 15% gelatin aqueous solution and the moistened purified micronized flavonoid component in a hot melt wet granulator, control the temperature of the hot melt wet granulator to 40° C., the stirring speed to 180 rpm, and the shear speed to 1800 rpm, and granulate the moistened purified micronized flavonoid component for 5 min;

[0116] (4) Wet granulation: The granules obtained in step 3) are wet granulated by a swing granulator (24 mesh screen);

[0117] (5) Drying: Place the wet granulated granules in an oven at 60°C and dry them until the moisture content is 3-4%. Then stop drying.

[0118] (6) Dry granulation: the dried granules are sieved through a 24-mesh screen;

[0119] (7) Total mixing: Add the dry whole granules and excipients (microcrystalline cellulose, sodium carboxymethyl starch, talc, and magnesium stearate) into a mixer and mix at 10 rpm for 10 min to ensure uniform mixing of the materials;

[0120] (8) Tabletting: Tableting is performed using a 16.5*8.3 mm special-shaped punch, with the tablet weight controlled to be 650 mg, the tablet weight variation within ±4%, and the hardness to be 10-15 kgf;

[0121] (9) Coating: Prepare coating solution according to solid content of 12%, control main machine speed at 12 rpm, fan speed at 1500 rpm, atomization pressure at 0.2 MPa, air inlet temperature at 65°C, pump speed at 1.5-2.5 rpm, coating weight gain at 2-3%, and continue drying in the pot for 30 min after coating.

[0122] Comparative Example 1

[0123] 1. Recipe:

[0124]

[0125]

[0126] 2. Preparation process:

[0127] (1) Material pretreatment: Place the purified micronized flavonoid component in a hot melt wet granulator, start stirring and shearing, control the stirring speed to 180 rpm, the shearing speed to 800 rpm, the temperature of the hot melt wet granulator to 40° C., and add ethanol to wet the purified micronized flavonoid component;

[0128] (2) Preparation of adhesive: using gelatin with a freezing strength of 240 BLoomg, prepare a gelatin aqueous solution with purified water at a concentration of 15%;

[0129] (3) Granulation: Place a 15% gelatin aqueous solution and the moistened purified micronized flavonoid component in a hot melt wet granulator, control the temperature of the hot melt wet granulator to 40° C., the stirring speed to 180 rpm, and the shear speed to 1600 rpm, and granulate the moistened purified micronized flavonoid component for 5 min;

[0130] (4) Wet granulation: The granules obtained in step 3) are wet granulated by a swing granulator (24 mesh screen);

[0131] (5) Drying: Place the wet granulated granules in an oven at 60°C and dry them until the moisture content is 3-4%. Then stop drying.

[0132] (6) Dry granulation: the dried granules are sieved through a 24-mesh screen;

[0133] (7) Total mixing: Add the dry whole granules and excipients (microcrystalline cellulose, sodium carboxymethyl starch, talc, and magnesium stearate) into a mixer and mix at 10 rpm for 10 min to ensure uniform mixing of the materials;

[0134] (8) Tabletting: Tableting is performed using a 16.5*8.3 mm special-shaped punch, with the tablet weight controlled to be 650 mg, the tablet weight variation within ±4%, and the hardness to be 10-15 kgf;

[0135] (9) Coating: Prepare coating solution according to solid content of 12%, control main machine speed at 12 rpm, fan speed at 1500 rpm, atomization pressure at 0.2 MPa, air inlet temperature at 65°C, pump speed at 1.5-2.5 rpm, coating weight gain at 2-3%, and continue drying in the pot for 30 min after coating.

[0136] Comparative Example 2

[0137] 1. Recipe:

[0138]

[0139] 2. Preparation process:

[0140] (1) Material pretreatment: Place the purified micronized flavonoid component in a hot melt wet granulator, start stirring and shearing, control the stirring speed to 180 rpm, the shearing speed to 800 rpm, and the temperature of the hot melt wet granulator to 40°C;

[0141] (2) Preparation of adhesive: using gelatin with a freezing strength of 120 BLoomg, prepare a gelatin aqueous solution with purified water at a concentration of 15%;

[0142] (2) Granulation: The temperature of the hot melt wet granulator was controlled at 40°C, the stirring speed was 180 rpm, and the shear speed was 1600 rpm to granulate the purified micronized flavonoid component. Gelatin was added until the granulation was completed for a total of 5 minutes;

[0143] (3) Wet granulation: The granules obtained in step 3) are wet granulated by a swing granulator (24 mesh screen);

[0144] (4) Drying: Place the wet granulated granules in an oven at 60°C and dry them until the moisture content is 3-4%. Then stop drying.

[0145] (5) Dry granulation: the dried granules are sieved through a 24-mesh screen;

[0146] (6) Total mixing: Add the dry whole granules and excipients (microcrystalline cellulose, sodium carboxymethyl starch, talc, and magnesium stearate) into a mixer and mix at 10 rpm for 10 min to ensure uniform mixing of the materials;

[0147] (7) Tabletting: Tableting is performed using a 16.5*8.3 mm special-shaped punch, with the tablet weight controlled at 650 mg, the tablet weight variation within ±4%, and the hardness at 10-15 kgf;

[0148] (8) Coating: Prepare coating solution according to solid content of 12%, control main machine speed at 12 rpm, fan speed at 1500 rpm, atomization pressure at 0.2 MPa, air inlet temperature at 65°C, pump speed at 1.5-2.5 rpm, coating weight gain at 2-3%, and continue drying in the pot for 30 min after coating.

[0149] Comparative Example 3

[0150] 1. Recipe:

[0151]

[0152] 2. Preparation process:

[0153] (1) Material pretreatment: Place the purified micronized flavonoid component in a wet granulator, start stirring and shearing, control the stirring speed to 180 rpm, the shearing speed to 800 rpm, and add ethanol to wet the purified micronized flavonoid component;

[0154] (2) Preparation of adhesive: using gelatin with a freezing strength of 120 BLoomg, prepare a gelatin aqueous solution with purified water at a concentration of 15%;

[0155] (3) Granulation: Place a 15% gelatin aqueous solution and the moistened purified micronized flavonoid component in a wet granulator, control the stirring speed to 180 rpm and the shear speed to 1600 rpm, and granulate the moistened purified micronized flavonoid component for 5 min;

[0156] (4) Wet granulation: The granules obtained in step 3) are wet granulated by a swing granulator (24 mesh screen);

[0157] (5) Drying: Place the wet granulated granules in an oven at 60°C and dry them until the moisture content is 3-4%. Then stop drying.

[0158] (6) Dry granulation: the dried granules are sieved through a 24-mesh screen;

[0159] (7) Total mixing: Add the dry whole granules and excipients (microcrystalline cellulose, sodium carboxymethyl starch, talc, and magnesium stearate) into a mixer and mix at 10 rpm for 10 min to ensure uniform mixing of the materials;

[0160] (8) Tabletting: Tableting is performed using a 16.5*8.3 mm special-shaped punch, with the tablet weight controlled to be 650 mg, the tablet weight variation within ±4%, and the hardness to be 10-15 kgf;

[0161] (9) Coating: Prepare coating solution according to solid content of 12%, control main machine speed at 12 rpm, fan speed at 1500 rpm, atomization pressure at 0.2 MPa, air inlet temperature at 65°C, pump speed at 1.5-2.5 rpm, coating weight gain at 2-3%, and continue drying in the pot for 30 min after coating.

[0162] Comparative Example 4

[0163] 1. Recipe:

[0164]

[0165] 2. Preparation process:

[0166] (1) Material pretreatment: Place the purified micronized flavonoid component in a wet granulator, start stirring and shearing, control the stirring speed to 180 rpm, the shearing speed to 800 rpm, and add ethanol to wet the purified micronized flavonoid component;

[0167] (2) Preparation of adhesive: using gelatin with a freezing strength of 120 BLoomg, prepare a gelatin aqueous solution with purified water at a concentration of 20%;

[0168] (3) Granulation: Place a 25% gelatin aqueous solution and the moistened purified micronized flavonoid component in a hot melt wet granulator, control the temperature of the hot melt wet granulator to 40° C., the stirring speed to 180 rpm, and the shear speed to 1600 rpm, and granulate the moistened purified micronized flavonoid component for 5 min;

[0169] (4) Wet granulation: The granules obtained in step 3) are wet granulated by a swing granulator (24 mesh screen);

[0170] (5) Drying: Place the wet granulated granules in an oven at 60°C and dry them until the moisture content is 3-4%. Then stop drying.

[0171] (6) Dry granulation: the dried granules are sieved through a 24-mesh screen;

[0172] (7) Total mixing: Add the dry whole granules and excipients (microcrystalline cellulose, sodium carboxymethyl starch, talc, and magnesium stearate) into a mixer and mix at 10 rpm for 10 min to ensure uniform mixing of the materials;

[0173] (8) Tabletting: Tableting is performed using a 16.5*8.3 mm special-shaped punch, with the tablet weight controlled to be 650 mg, the tablet weight variation within ±4%, and the hardness to be 10-15 kgf;

[0174] (9) Coating: Prepare coating solution according to solid content of 12%, control main machine speed at 12 rpm, fan speed at 1500 rpm, atomization pressure at 0.2 MPa, air inlet temperature at 65°C, pump speed at 1.5-2.5 rpm, coating weight gain at 2-3%, and continue drying in the pot for 30 min after coating.

[0175] Comparative Example 5

[0176] 1. Recipe:

[0177]

[0178] 2. Preparation process:

[0179] (1) Material pretreatment: Place the purified micronized flavonoid component in a hot melt wet granulator, start stirring and shearing, control the stirring speed to 180 rpm, the shearing speed to 800 rpm, the temperature of the hot melt wet granulator to 40° C., and add ethanol to wet the purified micronized flavonoid component;

[0180] (2) Preparation of adhesive: using gelatin with a freezing strength of 120 BLoomg, prepare a gelatin aqueous solution with purified water at a concentration of 15%;

[0181] (3) Granulation: spray a 15% gelatin aqueous solution into a hot melt wet granulator containing the moistened purified micronized flavonoid component, control the temperature of the hot melt wet granulator to 40°C, the stirring speed to 100 rpm, and the shear speed to 1600 rpm, and granulate the moistened purified micronized flavonoid component for 5 min;

[0182] (4) Wet granulation: The granules obtained in step 3) are wet granulated by a swing granulator (24 mesh screen);

[0183] (5) Drying: Place the wet granulated granules in an oven at 60°C and dry them until the moisture content is 3-4%. Then stop drying.

[0184] (6) Dry granulation: the dried granules are sieved through a 24-mesh screen;

[0185] (7) Total mixing: Add the dry whole granules and excipients (microcrystalline cellulose, sodium carboxymethyl starch, talc, and magnesium stearate) into a mixer and mix at 10 rpm for 10 min to ensure uniform mixing of the materials;

[0186] (8) Tabletting: Tableting is performed using a 16.5*8.3 mm special-shaped punch, with the tablet weight controlled to be 650 mg, the tablet weight variation within ±4%, and the hardness to be 10-15 kgf;

[0187] (9) Coating: Prepare coating solution according to solid content of 12%; control the main engine speed to 12 rpm, fan speed to 1500 rpm, atomization pressure to 0.2 MPa, air inlet temperature to 65°C, pump speed to 1.5-2.5 rpm, coating weight gain to 2-3%, and continue to dry in the pot for 30 min after coating.

[0188] Comparative Example 6

[0189] 1. Recipe:

[0190]

[0191] 2. Preparation process:

[0192] (1) Material pretreatment: Place the purified micronized flavonoid component in a hot melt wet granulator, start stirring and shearing, control the stirring speed to 180 rpm, the shearing speed to 800 rpm, the temperature of the hot melt wet granulator to 40° C., and add ethanol to wet the purified micronized flavonoid component;

[0193] (2) Preparation of adhesive: using gelatin with a freezing strength of 120 BLoomg, prepare a gelatin aqueous solution with purified water at a concentration of 15%;

[0194] (3) Granulation: spray a 15% gelatin aqueous solution into a hot melt wet granulator containing the moistened purified micronized flavonoid component, control the hot melt wet granulator temperature at 40°C, the stirring speed at 180 rpm, and the shear speed at 2400 rpm to granulate the moistened purified micronized flavonoid component, and run for 5 min to complete the granulation;

[0195] (4) Wet granulation: The granules obtained in step 3) are wet granulated by a swing granulator (24 mesh screen);

[0196] (5) Drying: Place the wet granulated granules in an oven at 60°C and dry them until the moisture content is 3-4%. Then stop drying.

[0197] (6) Dry granulation: the dried granules are sieved through a 24-mesh screen;

[0198] (7) Total mixing: Add the dry whole granules and excipients (microcrystalline cellulose, sodium carboxymethyl starch, talc, and magnesium stearate) into a mixer and mix at 10 rpm for 10 min to ensure uniform mixing of the materials;

[0199] (8) Tabletting: Tableting is performed using a 16.5*8.3 mm special-shaped punch, with the tablet weight controlled to be 650 mg, the tablet weight variation within ±4%, and the hardness to be 10-15 kgf;

[0200] (9) Coating: Prepare coating solution according to solid content of 12%; control the main engine speed to 12 rpm, fan speed to 1500 rpm, atomization pressure to 0.2 MPa, air inlet temperature to 65°C, pump speed to 1.5-2.5 rpm, coating weight gain to 2-3%, and continue to dry in the pot for 30 min after coating.

[0201] Comparative Example 7

[0202] 1. Recipe:

[0203]

[0204] 2. Preparation process:

[0205] (1) Material pretreatment: Place the purified micronized flavonoid component in a hot melt wet granulator, start stirring and shearing, control the stirring speed to 180 rpm, the shearing speed to 800 rpm, the temperature of the hot melt wet granulator to 40° C., and add ethanol to wet the purified micronized flavonoid component;

[0206] (2) Preparation of adhesive: using gelatin with a freezing strength of 120 BLoomg, prepare a gelatin aqueous solution with purified water at a concentration of 15%;

[0207] (3) Granulation: Spray a 15% gelatin aqueous solution into a hot melt wet granulator containing the moistened purified micronized flavonoid component. Control the temperature of the hot melt wet granulator at 35° C., the stirring speed at 180 rpm, and the shear speed at 1600 rpm to granulate the moistened purified micronized flavonoid component. The granulation is completed after running for 5 min.

[0208] (4) Wet granulation: The granules obtained in step 3) are wet granulated by a swing granulator (24 mesh screen);

[0209] (5) Drying: Place the wet granulated granules in an oven at 60°C and dry them until the moisture content is 3-4%. Then stop drying.

[0210] (6) Dry granulation: the dried granules are sieved through a 24-mesh screen;

[0211] (7) Total mixing: Add the dry whole granules and excipients (microcrystalline cellulose, sodium carboxymethyl starch, talc, and magnesium stearate) into a mixer and mix at 10 rpm for 10 min to ensure uniform mixing of the materials;

[0212] (8) Tabletting: Tableting is performed using a 16.5*8.3 mm special-shaped punch, with the tablet weight controlled to be 650 mg, the tablet weight variation within ±4%, and the hardness to be 10-15 kgf;

[0213] (9) Coating: Prepare coating solution according to solid content of 12%; control the main engine speed to 12 rpm, fan speed to 1500 rpm, atomization pressure to 0.2 MPa, air inlet temperature to 65°C, pump speed to 1.5-2.5 rpm, coating weight gain to 2-3%, and continue to dry in the pot for 30 min after coating.

[0214] The conditions of Examples 1-6 and Comparative Examples 1-7 during the preparation process are recorded, as shown in Table 1 below.

[0215] Table 1: Conditions of Examples 1-6 and Comparative Examples 1-7 during the preparation process

[0216]

[0217]

[0218] As shown in Table 1, when comparing Example 1 and Example 3 with Comparative Example 1, it can be found that the use of gelatin with a gelatin freezing force value greater than 120-150BLoomg will result in more solid particles after sieving and obvious flower pieces after tableting; when comparing Examples 1-6 with Comparative Example 2, it can be found that wetting the raw materials with ethanol before granulation can effectively improve the adhesion of the raw materials to the wall. It can be seen from Example 1 and Comparative Example 3 that the use of hot melt wet granulation can effectively ensure that the gelatin solution does not solidify during the entire granulation process, and fully wets the material to play a bonding role. Comparing Examples 1-6 with Comparative Examples 5-6, it can be found that the stirring speed and shear speed have no obvious effect on the process of this product. Comparing Example 1 with Comparative Example 7, a suitable temperature should be selected during the hot melt granulation process to ensure that the gelatin solution does not solidify during the granulation process.

[0219] Examples 1-6, Comparative Examples 1-7 and reference preparations (from Servier Pharmaceuticals, France) were compared. ) were compared with the disintegration time (37°C, water) (and the dissolution curve (0.15% sodium hydroxide + 1.5% TW80 medium, paddle method, 100rpm), and the results are as follows Figure 1 And as shown in Table 2.

[0220] Table 2 Disintegration time and dissolution curve results of Examples 1-6, Comparative Examples 1-7 and reference preparations

[0221]

[0222]

[0223] Depend on Figure 1 As shown in Table 2, the pharmaceutical compositions containing purified micronized flavonoid components of Examples 1-6 obtained according to the prescription and preparation process of the present invention have similar dissolution behaviors as the reference preparation in a 0.15% sodium hydroxide + 1.5% TW80 medium (paddle method 100 rpm), and have similar disintegration time as the reference preparation in a 37°C aqueous medium.

[0224] From the results of Example 1, Example 3 and Comparative Example 1, it can be seen that there is no obvious difference in the disintegration between Example 1 and Example 3 and between Comparative Example 1 and the reference preparation, but the dissolution of Comparative Example 1 is slower than that of Example 1 and Example 3, and is not similar to the reference preparation. The reason is that the viscosity of high freezing strength gelatin is higher, which leads to slower dissolution when high freezing strength gelatin is used as an adhesive.

[0225] Comparing the results of Examples 1-6 with Comparative Example 2, it can be seen that there is no obvious difference in the disintegration of Examples 1-6 and Comparative Example 2 and the reference. Whether the material is moistened with ethanol before granulation is not a key factor for the dissolution behavior of the product, but the dissolution rate of Comparative Example 2 is slightly faster than that of Examples 1-6. The reason is that the material cannot be completely moistened by gelatin after sticking to the wall, resulting in part of the material not completely forming particles and dissolving faster.

[0226] Comparing the results of Examples 1-6 with Comparative Example 3, it can be seen that the disintegration time of Comparative Example 3 is significantly faster than that of Examples 1-6 and the reference preparation. At the same time, Comparative Example 3 dissolves faster than Examples 1-6, which is different from the reference preparation. The reason is that the gelatin solidifies in the wet granulator and does not completely wet the material, resulting in more granular powder, which makes it dissolve faster, indicating that the product will not dissolve slower due to the use of wet granulation technology. The disintegration results of Examples 1-6 and Comparative Example 3 also show that the product prepared by the wet granulation process will not cause slow dissolution.

[0227] Comparing the results of Example 1, Example 2 and Comparative Example 4, it can be seen that the disintegration time of Comparative Example 4 is slower than that of Example 1, Example 2 and the reference preparation, and the dissolution rate of Comparative Example 4 is slower than that of Example 1 and Example 2, which is not similar to the reference preparation. In addition, the dissolution rate of Example 2 is slightly faster than that of Example 1, which indicates that as the concentration of gelatin increases, the dissolution behavior of this product will slow down.

[0228] By comparing the results of Example 5 with Comparative Example 5, it can be seen that the dissolution rate of Comparative Example 5 is faster than that of Example 5 and is different from that of the reference preparation. This may be because the stirring speed used in Comparative Example 5 is too low, which makes it impossible for the gelatin solution to be fully dispersed and difficult to fully exert its adhesive effect, resulting in too fast dissolution.

[0229] By comparing the results of Example 6 with Comparative Example 6, it can be seen that the dissolution rate of Comparative Example 6 is slower than that of Example 6 and is not similar to the reference preparation. The reason is that the shear speed is too fast, which makes the product particles prepared more solid, and the raw materials dissolve more slowly after the particles disintegrate.

[0230] By comparing the results of Example 1, Example 4 and Comparative Example 7, it can be seen that the dissolution behavior of Comparative Example 7 is significantly faster than that of Example 1 and Example 4 and is different from that of the reference preparation. The reason is that during the hot-melt granulation process, when the equipment maintains a temperature below 40°C, the gelatin solution is difficult to maintain a solution state and cannot fully wet the material.

[0231] from Figure 2 It can be seen that the comparison Figure 2 The plain tablets of Example 1 and Comparative Example 1 show that the pharmaceutical composition containing purified micronized flavonoid components prepared by the method of the present invention can effectively improve the plain tablet flakes caused by the excessive jelly value of gelatin. Figure 2It can be seen from the plain tablets of Example 1 and Comparative Example 3 that the hot melt wet granulation process can effectively improve the plain tablet flower phenomenon caused by traditional wet granulation.

[0232] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing a pharmaceutical composition containing purified micronized flavonoid components, characterized in that: The gelatin aqueous solution and the moistened purified micronized flavonoid component are placed in a hot melt wet granulator for granulation, the looseness of the particles is controlled by controlling the granulation parameters and the granulation time, and then the particles are mixed with auxiliary materials for tableting and coating to prepare a pharmaceutical composition containing the purified micronized flavonoid component; wherein the jelly strength value of the gelatin is 100-200 BLoomg, the concentration of the gelatin aqueous solution is 10-15%, and the mass ratio of the purified micronized flavonoid component to the gelatin is 100:2.5-10.

2. The method for preparing a pharmaceutical composition containing purified micronized flavonoid components according to claim 1, characterized in that: The temperature of the hot melt wet granulator was controlled at 40-70°C, the stirring speed was 120-200 rpm, the shearing speed was 1000-2000 rpm, and the granulation time was 5 min.

3. The method for preparing a pharmaceutical composition containing purified micronized flavonoid components according to claim 2, characterized in that: The temperature of the hot melt wet granulator was controlled to be 40°C, the stirring speed to be 180 rpm, the shearing speed to be 1600 rpm, and the granulation time to be 5 min.

4. The method for preparing a pharmaceutical composition containing purified micronized flavonoid components according to claim 1, characterized in that: The specific steps include: 1) Wetting the purified micronized flavonoid component with ethanol; 2) granulating the moistened purified micronized flavonoid component with gelatin; 3) subjecting the granules obtained by granulation to wet granulation, drying and dry granulation; 4) mixing a filler, a disintegrant and a lubricant with the dry granulated granules to obtain a total mixed granule; 5) The total mixed granules are tableted and coated to prepare a pharmaceutical composition containing purified micronized flavonoid components.

5. The method for preparing a pharmaceutical composition containing purified micronized flavonoid components according to claim 4, characterized in that: In the step 1), the volume fraction of ethanol is 50% to 100%, and the mass ratio of ethanol to the purified micronized flavonoid component is 10 to 20:

100.

6. The method for preparing a pharmaceutical composition containing purified micronized flavonoid components according to claim 4, characterized in that: In step 5), the total mixed granules are tableted with a special-shaped punch, the tablet weight difference is within ±4%, and the hardness is 10-15 kgf; the coating solution is prepared according to a solid content of 12%; the main engine speed is controlled to be 12 rpm, the fan speed is 1500 rpm, the atomization pressure is 0.2 MPa, the inlet air temperature is 65°C, the pump speed is 1.5-2.5 rpm, the coating weight gain is 2-3%, and the coating is carried out, and drying is continued for 30 minutes after the coating is completed.

7. The method for preparing a pharmaceutical composition containing a purified micronized flavonoid component according to any one of claims 1 to 6, wherein the pharmaceutical composition containing a purified micronized flavonoid component is prepared.

8. The pharmaceutical composition containing the purified micronized flavonoid component according to claim 7, characterized in that: The pharmaceutical composition consists of purified micronized flavonoid components, a binder, a filler, a disintegrant, a lubricant and purified water.

9. The pharmaceutical composition containing the purified micronized flavonoid component according to claim 8, characterized in that: The binder is gelatin; the filler is selected from one or more of microcrystalline cellulose, silicified microcrystalline cellulose, and mannitol; the disintegrant is selected from one or more of cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose; the lubricant is selected from one or more of magnesium stearate, talc, colloidal silicon dioxide, and sodium stearyl fumarate.

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