A method for preparing granisetron hydrochloride tablets with good uniformity

Abstract

The invention discloses a method for preparing a granisetron hydrochloride tablet with good uniformity, wherein the granisetron hydrochloride tablet is prepared from the following raw materials in parts by weight: 0.5 to 1.7 parts of granisetron hydrochloride, 80.4 to 102.4 parts of a filler, 2 to 7 parts of a disintegrant, 1 to 5 parts of a binder, and 0.6 to 1.4 parts of a lubricant. The invention provides a granisetron hydrochloride tablet with stable quality and good uniformity and a preparation method thereof, wherein the raw material drug granisetron hydrochloride excipients are uniformly mixed by premixing, wet granulation, and the like, thereby improving the uniformity and stability of the product.

Description

[0001] The present invention is a divisional application of 2023116207097, a stable granisetron hydrochloride tablet and a preparation method thereof, filed on November 30, 2023. Technical Field

[0002] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a method for preparing granisetron hydrochloride tablets with good uniformity. Background Art

[0003] Granisetron Hydrochloride, chemical name is 1-methyl-N-(endo-9-methyl-9-azabicyclo[3.3.1]nonane-3-yl)-1H-indazole-3-carboxamide hydrochloride, molecular formula is C 18 H 34 N4O·HCl, with a molecular weight of 348.87, is a selective 5-hydroxytryptamine (5-HT3) receptor antagonist used to treat nausea and vomiting caused by chemotherapy and radiotherapy, as well as to prevent nausea after surgery. Chemotherapy and radiotherapy can cause enterochromaffin cells to release 5-HT, which in turn activates 5-HT3 receptors and causes vomiting reflexes. Granisetron hydrochloride prevents and treats nausea and vomiting by antagonizing 5-HT3 receptors in the peripheral and central nervous systems.

[0004] Granisetron hydrochloride tablets were first developed by the British company SmithKline Beecham (now GlaxoSmithKline), and the tablets were first launched in Italy.

[0005] The active ingredient granisetron hydrochloride in granisetron hydrochloride tablets is 1 mg, which is a low drug loading tablet. Mixing uniformity is a problem that needs to be solved in the preparation process of granisetron hydrochloride tablets. In addition, according to the compound characteristics of granisetron hydrochloride, it has certain hygroscopicity and the critical relative humidity is 67%.

[0006] At present, most of the patents on the preparation method of granisetron hydrochloride tablets are orally disintegrating tablets, such as Chinese patent application number CN200310121906, which discloses a granisetron hydrochloride orally disintegrating tablet and its preparation method, using microcrystalline cellulose, cross-linked polyvinyl pyrrolidone, low-substituted polypropyl cellulose, cross-linked sodium carboxymethyl starch or their mixture as disintegrants, which is characterized by rapid disintegration in the oral cavity without the need for water or with only a small amount of water. Chinese patent application number CN201110176824 discloses a granisetron hydrochloride lyophilized tablet and its preparation method, using glycine or mannitol or their mixture, pullulan or sodium alginate or their mixture as skeleton support and adhesive, and obtaining a granisetron hydrochloride lyophilized tablet by pre-freezing and freeze-drying the prepared matrix liquid, which is characterized by rapid disintegration in the oral cavity without the need for water.

[0007] However, the orally disintegrating tablets obtained by tableting or freeze drying all have little hardness due to the characteristics of the process, low mechanical strength, and high friability, which brings strict production technology and condition requirements, and strict requirements are all provided in the processes such as packaging, storage and transportation, and the cost is high, which limits the wide application of the product. Therefore, it is still necessary to develop a stable granisetron hydrochloride tablet with simple preparation technology and good mixing uniformity, and a moisture-proof and light-proof packaging method. Previously, there was no patent for the preparation method of granisetron hydrochloride oral solid tablets published, etc. Summary of the invention

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

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

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

[0011] In some embodiments, the granisetron hydrochloride tablets are made of the following raw materials in parts by weight:

[0012]

[0013] Wherein, the filler includes lactose.

[0014] In some embodiments, the granisetron hydrochloride tablets are made of the following raw materials in parts by weight:

[0015]

[0016] Wherein, the filler includes lactose.

[0017] In some embodiments, the granisetron hydrochloride tablets are made of the following raw materials in parts by weight:

[0018]

[0019] Wherein, the filler includes lactose.

[0020] In some embodiments, the raw materials for preparing the granisetron hydrochloride tablets also include coating materials; preferably, the weight ratio of the granisetron hydrochloride to the coating materials is 0.5-1.7:2-4, preferably 0.8-1.4:2.5-3.5, preferably 1.1:3.

[0021] In some embodiments, the granisetron hydrochloride tablets are prepared by the following method:

[0022] (1) mixing the granisetron hydrochloride API with a portion of lactose to obtain a premix; the portion of lactose being 40% to 60% of the total mass of the lactose;

[0023] (2) mixing the remaining lactose and other fillers with the obtained premix to obtain a mixture;

[0024] (3) wet granulating the obtained mixture with a disintegrant and a binder solution to obtain an intermediate;

[0025] (4) mixing the obtained intermediate with a lubricant and tableting;

[0026] (5) coating the obtained plain tablet with a coating material;

[0027] (6) After coating, polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard tablets and pharmaceutical aluminum foil are used for packaging.

[0028] In a second aspect, the present invention discloses a method for preparing granisetron hydrochloride tablets.

[0029] In some embodiments, the granisetron hydrochloride tablets are made of the following raw materials in parts by weight:

[0030]

[0031] Wherein, the filler includes lactose.

[0032] In some embodiments, the granisetron hydrochloride tablets are made of the following raw materials in parts by weight:

[0033]

[0034] Wherein, the filler includes lactose.

[0035] In some embodiments, the granisetron hydrochloride tablets are made of the following raw materials in parts by weight:

[0036]

[0037]

[0038] Wherein, the filler includes lactose.

[0039] In some embodiments, the raw materials for preparing the granisetron hydrochloride tablets also include coating materials; preferably, the weight ratio of the granisetron hydrochloride to the coating materials is 0.5-1.7:2-4, preferably 0.8-1.4:2.5-3.5, preferably 1.1:3.

[0040] In some embodiments, the preparation method of the granisetron hydrochloride tablets comprises the following steps:

[0041] (1) crushing the granisetron hydrochloride raw material and mixing it with a portion of lactose to obtain a premix; the portion of lactose is 40% to 60% of the total mass of the lactose;

[0042] (2) mixing the remaining lactose and other fillers with the obtained premix to obtain a mixture;

[0043] (3) wet granulating the obtained mixture with a disintegrant and a binder solution to obtain an intermediate;

[0044] (4) mixing the obtained intermediate with a lubricant and tableting;

[0045] (5) coating the obtained plain tablet with a coating material;

[0046] (6) After coating, polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard tablets and pharmaceutical aluminum foil are used for packaging.

[0047] In the above-mentioned first and second technical problems,

[0048] The granisetron hydrochloride is obtained by crushing the granisetron hydrochloride raw material through a 60-80 mesh sieve; preferably, the D90 of the granisetron hydrochloride is 10 μm to 20 μm; preferably, the D50 of the granisetron hydrochloride is above 10 μm.

[0049] The filler also includes starch and / or microcrystalline cellulose, preferably microcrystalline cellulose; preferably, the mass ratio of the starch and / or microcrystalline cellulose to lactose is 1:1.1-4.3, preferably 1:1.3-3.8, preferably 1:1.5-3.3; preferably, the particle size of the lactose is less than 90 μm; preferably, the particle size of the starch and microcrystalline cellulose is 40-80 μm.

[0050] The disintegrant is any one or more combinations of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethyl cellulose, preferably sodium carboxymethyl starch, preferably sodium carboxymethyl starch with a sodium content of 2.0% to 4.0%.

[0051] The binder is any one or more combinations of hydroxypropyl cellulose, ethyl cellulose and hydroxypropyl methyl cellulose, preferably hydroxypropyl methyl cellulose, and preferably a binder with a viscosity of 3 to 20 cPs.

[0052] The lubricant is any one or more combinations of stearic acid, magnesium stearate and sodium stearyl fumarate, preferably magnesium stearate, and preferably a lubricant that passes through a 60-80 mesh sieve.

[0053] The coating material is a gastric soluble film coating premix.

[0054] In step (1), the partial lactose is 45%-55% of the total mass of lactose, preferably 50%.

[0055] In step (2), the premix is ​​sieved through a 30-mesh sieve in a granulator, the remaining lactose is added and sieved repeatedly for 2 to 5 times, and then the remaining fillers are added and sieved to obtain a mixture; the rotation speed is 800 to 1200 rpm, preferably 1000 rpm.

[0056] In step (3), the binder solution is an aqueous solution of a binder; the solid content of the binder in the binder solution is 3% g / ml to 13% g / ml, preferably 5% g / ml to 10% g / ml, preferably 7% g / ml.

[0057] In step (3), the wet granulation is performed in a wet granulator by premixing the obtained mixture with a disintegrant, adding a binder solution to prepare a soft material, wet granulation, drying and dry granulation; preferably, during the premixing, the rotation speed of the stirring blade is 90-120 rpm, and the rotation speed of the chopping blade is 800-1000 rpm; preferably, during the preparation of the soft material, the rotation speed of the stirring blade is 100-150 rpm, the rotation speed of the chopping blade is 1000-1500 rpm, and the mixing time is more than 10 minutes; preferably, during the wet granulation, the mesh aperture is 3 mm; preferably, during the dry granulation, the mesh aperture is 1 mm; preferably, the drying temperature is 40-50°C.

[0058] In step (4), the mixing is performed in a mixer for 1 to 3 times; preferably, the charging factor of the mixer is 45% to 70%; preferably, during mixing, the rotation speed of the mixer is 10 to 20 rpm; preferably, the mixing time is 1 to 5 min; preferably, during the tableting process, the ambient humidity is controlled below 65%, such as 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, etc.; preferably, during the tableting process, the tablet weight difference is controlled to be ±5%, and the hardness is controlled to be 3.0 to 6.0 kg.

[0059] In step (5), the weight gain after coating is 2.0% to 5.0%.

[0060] Beneficial effects:

[0061] The invention provides a granisetron hydrochloride tablet with stable quality and good uniformity and a preparation method thereof. The raw material granisetron hydrochloride and auxiliary materials are uniformly mixed by premixing, wet granulation and other methods, thereby improving the uniformity and stability of the product. BRIEF DESCRIPTION OF THE DRAWINGS

[0062] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more clear.

[0063] Figure 1 It is the dissolution curve diagram of Example 1 and Comparative Examples 1-4. DETAILED DESCRIPTION

[0064] The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials described are commercially available unless otherwise specified.

[0065] The invention provides a stable granisetron hydrochloride tablet, the tablet weight of which is designed to be 104 mg. Excluding the active ingredient of granisetron hydrochloride, a large amount of auxiliary materials is required. The lactose used in the invention is spray-dried lactose with a particle size of less than 90 μm, the particle size of microcrystalline cellulose is 40-80 μm, and the viscosity of hypromellose is 3-20 cPs. The dosages thereof are all within the ranges published in the FDA inactive ingredient database (Inactive Ingredient Search for Approved Drug Products).

[0066] Hydroxypropyl methylcellulose is an excellent water-soluble adhesive and gastric-soluble coating material. It is obtained by chemically modifying natural cellulose. Its water solubility and stability are greatly improved compared to natural cellulose. It has the characteristics and uses of emulsification, bonding, gelation, suspension, viscosity enhancement and film formation, and has been widely used in the pharmaceutical field. Hydroxypropyl methylcellulose has strong viscosity, which can enhance the viscosity of raw material particles and improve its compressibility; its aqueous solution has excellent film-forming properties, and the film formed is colorless and tough, with stable chemical properties. As an isolation layer, it can greatly improve the stability of the drug and is a good coating material for tablets.

[0067] Sodium starch glycolate is a commonly used tablet disintegrant with excellent performance. It has a very significant water absorption and swelling effect, which can swell to 300 times its original volume. It does not form a colloidal solution and will not hinder the continued penetration of water, so the further disintegration of the tablet will not be affected.

[0068] Magnesium stearate has good lubricating effect and can be easily mixed with particles evenly, which can make the surface of tablets smooth and beautiful. It has no incompatibility with granisetron and has good compatibility.

[0069] The 50% lactose in the formula described in the present invention, unless otherwise specified, refers to 50% of the total mass of lactose in the formula.

[0070] The unit of solid content in the present invention is g / ml.

[0071] The film coating premix described in the following examples is the gastric soluble film coating premix YS-1-7-003-CN produced by Colorcon.

[0072] The sodium content of sodium carboxymethyl starch described in the following examples is 3.2%.

[0073] The parameter conditions of the hammer mill crushing described in the following embodiments are 7000-9000rpm, which can be specifically adjusted according to the particle size requirements.

[0074] Example 1

[0075] A method for preparing stable granisetron hydrochloride tablets, comprising the following steps when producing 10,000 tablets:

[0076] (1) Pretreatment of raw materials and excipients: weigh the raw materials and excipients according to the weight ratio, including 1.1 parts of granisetron hydrochloride, 69.4 parts of lactose, 23 parts of microcrystalline cellulose, 4 parts of sodium carboxymethyl starch, 2 parts of hypromellose, 1 part of magnesium stearate, and 3 parts of film coating premix. Among them, the particle size of lactose is less than 90 μm, the particle size of microcrystalline cellulose is 40-60 μm, and the viscosity of hypromellose is 4.9 mP.s. Granisetron hydrochloride raw material is crushed into fine powder using a hammer mill, passed through a 60-mesh sieve, D90 is 10 μm-20 μm, and D50 is greater than 10 μm, and then mixed with 50% of the formula amount of lactose to obtain granisetron hydrochloride lactose premix. Magnesium stearate is passed through a 60-mesh sieve. Binder preparation: Take the formula amount of hypromellose and purified water and put them in a beaker to prepare a binder solution with a solid content (g / ml) of 7%.

[0077] (2) Mixing and granulating: The granisetron hydrochloride lactose premix in step (1) is passed through a 30-mesh sieve in a rotary granulator, and the remaining lactose is continuously put into the rotary granulator and sieved three times. The microcrystalline cellulose is again put into the rotary granulator for granulation at a speed of 1000 rpm to obtain a granisetron hydrochloride lactose microcrystalline cellulose mixture.

[0078] (3) Granulation: The granisetron hydrochloride lactose microcrystalline cellulose mixture and sodium starch glycolate in step (2) are added to a wet granulator for premixing, the stirring blade speed is 100 rpm, the chopping blade speed is 900 rpm, and the binder solution prepared in step (1) is added after the premixing is completed to prepare a soft material. When preparing the soft material, the stirring blade speed is 130 rpm, the chopping blade speed is 1200 rpm, and the granulation is performed for 15 minutes. The wet granulation is performed using a 3 mm screen by a mobile granulator, and the mixture is placed in an oven at 50° C. and dried to a moisture content of less than 3%, and then dry granulated by passing through a 1 mm screen.

[0079] (4) Total mixing: Add the intermediate obtained in step (3) into the total mixer, add the formulated amount of magnesium stearate and mix at 12 rpm for 2 minutes. The charging factor is 45% to 70%.

[0080] (5) Tableting: The intermediate obtained in step (4) is placed in a mold for tableting. The ambient humidity is 53%. The tablet weight is calculated based on the intermediate content result. The tablet weight difference is controlled within ±5%, and the hardness is 3.0-6.0 kg / mm.

[0081] (6) Coating: Take a proper amount of coating liquid prepared from the gastric soluble film coating premix of Colorcon Company YS-1-7-003-CN, and add the plain tablets obtained in step (5) into the coating machine for coating. The coating weight gain is 2.0% to 5.0%.

[0082] (7) Packaging: Polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard tablets and pharmaceutical aluminum foil packaging.

[0083] Example 2

[0084] A method for preparing stable granisetron hydrochloride tablets, comprising the following steps when producing 10,000 tablets:

[0085] (1) Pretreatment of raw materials and excipients: weigh the raw materials and excipients according to the weight ratio, including 1.1 parts of granisetron hydrochloride, 55.4 parts of lactose, 37 parts of microcrystalline cellulose, 4 parts of sodium carboxymethyl starch, 2 parts of hypromellose, 1 part of magnesium stearate, and 3 parts of film coating premix. Among them, the particle size of lactose is less than 90 μm, the particle size of microcrystalline cellulose is 40-60 μm, and the viscosity of hypromellose is 4.9 mP.s. Granisetron hydrochloride raw material is crushed into micro powder using a hammer mill, passed through a 60-mesh sieve, D90 is 10 μm-20 μm, and D50 is greater than 10 μm, and then mixed with 50% of the formula amount of lactose to obtain granisetron hydrochloride lactose premix. Magnesium stearate is passed through a 60-mesh sieve. Binder preparation: Take the formula amount of hypromellose and purified water and put them in a beaker to prepare a binder solution with a solid content (g / ml) of 7%.

[0086] (2) Mixing and granulating: The granisetron hydrochloride lactose premix in step (1) is passed through a 30-mesh sieve in a rotary granulator, and the remaining lactose is continuously put into the rotary granulator and sieved three times. The microcrystalline cellulose is again put into the rotary granulator for granulation at a speed of 1000 rpm to obtain a granisetron hydrochloride lactose microcrystalline cellulose mixture.

[0087] (3) Granulation: The granisetron hydrochloride lactose microcrystalline cellulose mixture and sodium starch glycolate in step (2) are added to a wet granulator for premixing, the stirring blade speed is 100 rpm, the chopping blade speed is 900 rpm, and the binder solution prepared in step (1) is added after the premixing is completed to prepare a soft material. When preparing the soft material, the stirring blade speed is 130 rpm, the chopping blade speed is 1200 rpm, and the granulation is performed for 15 minutes. The wet granulation is performed using a 3 mm screen by a mobile granulator, and the mixture is placed in an oven at 50° C. and dried to a moisture content of less than 3%, and then dry granulated by passing through a 1 mm screen.

[0088] (4) Total mixing: Add the intermediate obtained in step (3) into the total mixer, add the formulated amount of magnesium stearate and mix at 12 rpm for 2 minutes. The charging factor is 45% to 70%.

[0089] (5) Tableting: The intermediate obtained in step (4) is placed in a mold for tableting. The ambient humidity is 57%. The tablet weight is calculated based on the intermediate content result. The tablet weight difference is controlled within ±5%, and the hardness is 3.0-6.0 kg / mm.

[0090] (6) Coating: Take a proper amount of coating liquid prepared from the gastric soluble film coating premix of Colorcon Company YS-1-7-003-CN, and add the plain tablets obtained in step (5) into the coating machine for coating. The coating weight gain is 2.0% to 5.0%.

[0091] (7) Packaging: Polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard tablets and pharmaceutical aluminum foil packaging.

[0092] Example 3

[0093] A method for preparing stable granisetron hydrochloride tablets, comprising the following steps when producing 10,000 tablets:

[0094] (1) Pretreatment of raw materials and excipients: weigh the raw materials and excipients according to the weight ratio, including 1.1 parts of granisetron hydrochloride, 69.4 parts of lactose, 21 parts of microcrystalline cellulose, 5 parts of sodium carboxymethyl starch, 3 parts of hypromellose, 1 part of magnesium stearate, and 3 parts of film coating premix. Among them, the particle size of lactose is less than 90 μm, the particle size of microcrystalline cellulose is 40-60 μm, and the viscosity of hypromellose is 4.9 mP.s. Granisetron hydrochloride raw material is crushed into fine powder using a hammer mill, passed through a 60-mesh sieve, D90 is 10 μm-20 μm, and D50 is greater than 10 μm, and then mixed with 50% of the formula amount of lactose to obtain granisetron hydrochloride lactose premix. Magnesium stearate is passed through a 60-mesh sieve. Binder preparation: Take the formula amount of hypromellose and purified water and put them in a beaker to prepare a binder solution with a solid content (g / ml) of 7%.

[0095] (2) Mixing and granulating: The granisetron hydrochloride lactose premix in step (1) is passed through a 30-mesh sieve in a rotary granulator, and the remaining lactose is continuously put into the rotary granulator and sieved three times. The microcrystalline cellulose is again put into the rotary granulator for granulation at a speed of 1000 rpm to obtain a granisetron hydrochloride lactose microcrystalline cellulose mixture.

[0096] (3) Granulation: The granisetron hydrochloride lactose microcrystalline cellulose mixture and sodium starch glycolate in step (2) are added to a wet granulator for premixing, the stirring blade speed is 100 rpm, the chopping blade speed is 900 rpm, and the binder solution prepared in step (1) is added after the premixing is completed to prepare a soft material. When preparing the soft material, the stirring blade speed is 130 rpm, the chopping blade speed is 1200 rpm, and the granulation is performed for 15 minutes. The wet granulation is performed using a 3 mm screen by a mobile granulator, and the mixture is placed in an oven at 50° C. and dried to a moisture content of less than 3%, and then dry granulated by passing through a 1 mm screen.

[0097] (4) Total mixing: Add the intermediate obtained in step (3) into the total mixer, add the formulated amount of magnesium stearate and mix at 12 rpm for 2 minutes. The charging factor is 45% to 70%.

[0098] (5) Tableting: The intermediate obtained in step (4) is placed in a mold for tableting. The ambient humidity is 52%. The tablet weight is calculated based on the intermediate content result. The tablet weight difference is controlled within ±5%, and the hardness is 3.0-6.0 kg / mm.

[0099] (6) Coating: Take a proper amount of coating liquid prepared from the gastric soluble film coating premix of Colorcon Company YS-1-7-003-CN, and add the plain tablets obtained in step (5) into the coating machine for coating. The coating weight gain is 2.0% to 5.0%.

[0100] (7) Packaging: Polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard tablets and pharmaceutical aluminum foil packaging.

[0101] Comparative Example 1

[0102] A method for preparing granisetron hydrochloride tablets by wet granulation, which comprises the following steps when producing 10,000 tablets:

[0103] (1) Pretreatment of raw materials and excipients: weigh the raw materials and excipients according to the weight ratio, including 1.1 parts of granisetron hydrochloride, 69.4 parts of lactose, 21 parts of microcrystalline cellulose, 5 parts of sodium carboxymethyl starch, 3 parts of hypromellose, 1 part of magnesium stearate, and 3 parts of film coating premix. Among them, the particle size of lactose is less than 90 μm, the particle size of microcrystalline cellulose is 40-60 μm, and the viscosity of hypromellose is 4.9 mP.s. Granisetron hydrochloride raw material is crushed into micro powder using a hammer mill, passed through a 60-mesh sieve, D90 is 10 μm-20 μm, and D50 is greater than 10 μm. Magnesium stearate is passed through a 60-mesh sieve. Binder preparation: Take the formulated amount of hypromellose and purified water and put them into a beaker to prepare a binder solution with a solid content (g / ml) of 7%.

[0104] (2) Mixing and granulating: The granisetron hydrochloride in step (1) is passed through a 30-mesh sieve in a rotary granulator, lactose is put into a rotary granulator, and microcrystalline cellulose is put into a rotary granulator for granulation, with the rotation speed of 1000 rpm to obtain granisetron hydrochloride, lactose, and microcrystalline cellulose, respectively.

[0105] (3) Granulation: Granisetron hydrochloride, lactose, microcrystalline cellulose and sodium starch glycolate in step (2) are added to a wet granulator for premixing, the stirring blade speed is 100 rpm, the chopping blade speed is 900 rpm, and after the premixing, the binder solution prepared in step (1) is added to prepare a soft material, the stirring blade speed is 130 rpm, the chopping blade speed is 1200 rpm, and the granulation is performed for 15 minutes. The wet granulation is performed using a mobile granulator using a 3 mm screen, and the mixture is placed in an oven at 50° C. and dried to a moisture content of less than 3%, and then dry granulated through a 1 mm screen.

[0106] (4) Total mixing: Add the intermediate obtained in step (3) into the total mixer, add the formulated amount of magnesium stearate and mix at 12 rpm for 2 minutes. The charging factor is 45% to 70%.

[0107] (5) Tableting: The intermediate obtained in step (4) is placed in a mold for tableting. The ambient humidity is 52%. The tablet weight is calculated based on the intermediate content result. The tablet weight difference is controlled within ±5%, and the hardness is 3.0-6.0 kg / mm.

[0108] (6) Coating: Take a proper amount of coating liquid prepared from the gastric soluble film coating premix of Colorcon Company YS-1-7-003-CN, and add the plain tablets obtained in step (5) into the coating machine for coating. The coating weight gain is 2.0% to 5.0%.

[0109] (7) Packaging: Polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard tablets and pharmaceutical aluminum foil packaging.

[0110] Comparative Example 2

[0111] The particle size of the granisetron hydrochloride raw material after crushing is larger than that in Example 1. When producing 10,000 tablets, the method includes the following steps:

[0112] (1) Pretreatment of raw materials and excipients: weigh the raw materials and excipients according to the weight ratio, including 1.1 parts of granisetron hydrochloride, 69.4 parts of lactose, 23 parts of microcrystalline cellulose, 4 parts of sodium carboxymethyl starch, 2 parts of hypromellose, 1 part of magnesium stearate, and 3 parts of film coating premix. Among them, the particle size of lactose is less than 90 μm, the particle size of microcrystalline cellulose is 40-60 μm, and the viscosity of hypromellose is 4.9 mP.s. Granisetron hydrochloride raw material is crushed into micro powder using a hammer mill, passed through a 60-mesh sieve, D90 is 40 μm-60 μm, and D50 is greater than 20 μm, and then mixed with 50% of the formula amount of lactose to obtain granisetron hydrochloride lactose premix. Magnesium stearate is passed through a 60-mesh sieve. Binder preparation: Take the formula amount of hypromellose and purified water and put them in a beaker to prepare a binder solution with a solid content (g / ml) of 7%.

[0113] (2) Mixing and granulating: The granisetron hydrochloride lactose premix in step (1) is passed through a 30-mesh sieve in a rotary granulator, and the remaining lactose is continuously put into the rotary granulator and sieved three times. The microcrystalline cellulose is again put into the rotary granulator for granulation at a speed of 1000 rpm to obtain a granisetron hydrochloride lactose microcrystalline cellulose mixture.

[0114] (3) Granulation: The granisetron hydrochloride lactose microcrystalline cellulose mixture and sodium starch glycolate in step (2) are added to a wet granulator for premixing, the stirring blade speed is 100 rpm, the chopping blade speed is 900 rpm, and the binder solution prepared in step (1) is added after the premixing is completed to prepare a soft material. When preparing the soft material, the stirring blade speed is 130 rpm, the chopping blade speed is 1200 rpm, and the granulation is performed for 15 minutes. The wet granulation is performed using a 3 mm screen by a mobile granulator, and the mixture is placed in an oven at 50° C. and dried to a moisture content of less than 3%, and then dry granulated by passing through a 1 mm screen.

[0115] (4) Total mixing: Add the intermediate obtained in step (3) into the total mixer, add the formulated amount of magnesium stearate and mix at 12 rpm for 2 minutes. The charging factor is 45% to 70%.

[0116] (5) Tableting: The intermediate obtained in step (4) is placed in a mold for tableting. The ambient humidity is 55%. The tablet weight is calculated based on the intermediate content result. The tablet weight difference is controlled within ±5%, and the hardness is 3.0-6.0 kg / mm.

[0117] (6) Coating: Take a proper amount of coating liquid prepared from the gastric soluble film coating premix of Colorcon Company YS-1-7-003-CN, and add the plain tablets obtained in step (5) into the coating machine for coating. The coating weight gain is 2.0% to 5.0%.

[0118] (7) Packaging: Polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard tablets and pharmaceutical aluminum foil packaging.

[0119] Comparative Example 3

[0120] The particle size of granisetron hydrochloride after crushing is smaller than that in the embodiment. When producing 10,000 tablets, the method comprises the following steps:

[0121] (1) Pretreatment of raw materials and excipients: weigh the raw materials and excipients according to the weight ratio, including 1.1 parts of granisetron hydrochloride, 69.4 parts of lactose, 23 parts of microcrystalline cellulose, 4 parts of sodium carboxymethyl starch, 2 parts of hypromellose, 1 part of magnesium stearate, and 3 parts of film coating premix. Among them, the particle size of lactose is less than 90 μm, the particle size of microcrystalline cellulose is 40-60 μm, and the viscosity of hypromellose is 4.9 mP.s. Granisetron hydrochloride raw material is crushed into fine powder using a jet mill, passed through a 60-mesh sieve, D90 is less than 9 μm, and D50 is less than 5 μm, and then mixed with 50% of the formula amount of lactose to obtain granisetron hydrochloride lactose premix. Magnesium stearate is passed through a 60-mesh sieve. Binder preparation: Take the formula amount of hypromellose and purified water and put them in a beaker to prepare a binder solution with a solid content (g / ml) of 7%.

[0122] (2) Mixing and granulating: The granisetron hydrochloride lactose premix in step (1) is passed through a 30-mesh sieve in a rotary granulator, and the remaining lactose is continuously put into the rotary granulator and sieved three times. The microcrystalline cellulose is again put into the rotary granulator for granulation at a speed of 1000 rpm to obtain a granisetron hydrochloride lactose microcrystalline cellulose mixture.

[0123] (3) Granulation: The granisetron hydrochloride lactose microcrystalline cellulose mixture and sodium starch glycolate in step (2) are added to a wet granulator for premixing, the stirring blade speed is 100 rpm, the chopping blade speed is 900 rpm, and the binder solution prepared in step (1) is added after the premixing is completed to prepare a soft material. When preparing the soft material, the stirring blade speed is 130 rpm, the chopping blade speed is 1200 rpm, and the granulation is performed for 15 minutes. The wet granulation is performed using a 3 mm screen by a mobile granulator, and the mixture is placed in an oven at 50° C. and dried to a moisture content of less than 3%, and then dry granulated by passing through a 1 mm screen.

[0124] (4) Total mixing: Add the intermediate obtained in step (3) into the total mixer, add the formulated amount of magnesium stearate and mix at 12 rpm for 2 minutes. The charging factor is 45% to 70%.

[0125] (5) Tableting: The intermediate obtained in step (4) is placed in a mold for tableting. The ambient humidity is 54%. The tablet weight is calculated based on the intermediate content result. The tablet weight difference is controlled within ±5%. The hardness is 3.0-6.0 kg / mm.

[0126] (6) Coating: Take a proper amount of coating liquid prepared from the gastric soluble film coating premix of Colorcon Company YS-1-7-003-CN, and add the plain tablets obtained in step (5) into the coating machine for coating. The coating weight gain is 2.0% to 5.0%.

[0127] (7) Packaging: Polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard tablets and pharmaceutical aluminum foil packaging.

[0128] Comparative Example 4

[0129] Granisetron hydrochloride tablets, in which microcrystalline cellulose is replaced with corn starch, include the following steps when producing 10,000 tablets:

[0130] (1) Pretreatment of raw materials and excipients: weigh the raw materials and excipients according to the weight ratio, including 1.1 parts of granisetron hydrochloride, 69.4 parts of lactose, 23 parts of corn starch, 4 parts of sodium carboxymethyl starch, 2 parts of hypromellose, 1 part of magnesium stearate, and 3 parts of film coating premix. Among them, the particle size of lactose is less than 90 μm, the particle size of corn starch is 40-80 μm, and the viscosity of hypromellose is 4.9 mP.s. Granisetron hydrochloride raw material is crushed into fine powder using a hammer mill, passed through a 60-mesh sieve, D90 is 10 μm-20 μm, and D50 is greater than 10 μm, and then mixed with 50% of the formula amount of lactose to obtain granisetron hydrochloride lactose premix. Magnesium stearate is passed through a 60-mesh sieve. Binder preparation: Take the formula amount of hypromellose and purified water and put them in a beaker to prepare a binder solution with a solid content (g / ml) of 7%.

[0131] (2) Mixing and granulating: The granisetron hydrochloride lactose premix in step (1) is passed through a 30-mesh sieve in a rotary granulator, and the remaining lactose is continuously put into the rotary granulator and sieved three times. The corn starch is again put into the rotary granulator for granulation at a speed of 1000 rpm to obtain a granisetron hydrochloride lactose corn starch mixture.

[0132] (3) Granulation: The granisetron hydrochloride lactose corn starch mixture and sodium carboxymethyl starch in step (2) are added to a wet granulator for premixing, the stirring blade speed is 100 rpm, the chopping blade speed is 900 rpm, and the binder solution prepared in step (1) is added after the premixing is completed to prepare a soft material. When preparing the soft material, the stirring blade speed is 130 rpm, the chopping blade speed is 1200 rpm, and the granulation is performed for 15 minutes. The wet granulation is performed using a 3 mm screen by a mobile granulator, and the mixture is placed in an oven at 50° C. and dried to a moisture content of less than 3%, and then dry granulated by passing through a 1 mm screen.

[0133] (4) Total mixing: Add the intermediate obtained in step (3) into the total mixer, add the formulated amount of magnesium stearate and mix at 12 rpm for 2 minutes. The charging factor is 45% to 70%.

[0134] (5) Tableting: The intermediate obtained in step (4) is placed in a mold for tableting. The ambient humidity is 59%. The tablet weight is calculated based on the intermediate content result. The tablet weight difference is controlled within ±5%, and the hardness is 3.0-6.0 kg / mm.

[0135] (6) Coating: Take a proper amount of coating liquid prepared from the gastric soluble film coating premix of Colorcon Company YS-1-7-003-CN, and add the plain tablets obtained in step (5) into the coating machine for coating. The coating weight gain is 2.0% to 5.0%.

[0136] (7) Packaging: Polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard tablets and pharmaceutical aluminum foil packaging.

[0137] Test 1

[0138] The product of Example 1 was subjected to content uniformity measurement, and the experimental results are shown in the following table. The RSD of the sample measurement results of the three batches of content uniformity of this product should be less than 3.0%, and the content uniformity meets the requirements; the content uniformity of Examples 2 and 3 was measured, and the experimental results showed that the RSD of the measurement results of the samples of Examples 2 and 3 was 1.2% to 1.6%, and the content uniformity met the requirements.

[0139] Sample batch number 01 02 03 1 101.80％ 102.43％ 102.11％ 2 99.35％ 101.36％ 99.67％ 3 99.23％ 98.92％ 99.17％ 4 101.05％ 102.30％ 101.62％ 5 99.17％ 98.73％ 101.67％ 6 101.61％ 100.73％ 100.86％ 7 99.54％ 101.98％ 99.29％ 8 101.05％ 98.67％ 100.86％ 9 98.86％ 100.92％ 98.92％ 10 101.36％ 98.29％ 101.98％ X bar 100.30％ 100.43％ 100.62％ RSD 1.2％ 1.6％ 1.2％

[0140] Note: X bar: average value of the contents of 10 tablets; RSD (%): formula for determining the uniformity of powder content.

[0141] Test 2

[0142] The product of Example 1 was subjected to a 10-day study of influencing factors (high temperature 40°C / 60°C, illumination 4500±500lux / h, high humidity RH75% / RH92.5%), an accelerated stability test (40°C / 75%) for 6 months, and a long-term stability test (30°C / 65%) for 24 months, and the properties, solubility (measured using a paddle method at 50rpm, 900ml of pH6.8 phosphate buffer, and Chinese Pharmacopoeia dissolution apparatus 2 at 37°C), related substances, and content were compared.

[0143] Results The properties and contents of the homemade products at each time point were in compliance with the regulations.

[0144]

[0145]

[0146] Test 3

[0147] The multi-media dissolution curve of the sample prepared in Example 1 was measured by using a paddle method at 50 rpm, 900 ml of pH 6.8 phosphate buffer, and a Chinese Pharmacopoeia dissolution apparatus 2 at 37° C. The experimental results showed that the preparation of the present invention had good dissolution uniformity and uniform dissolution, and the dissolution curves of the three batches of samples all met the requirements.

[0148]

[0149] The products obtained in Comparative Examples 1-4 were tested:

[0150] 1. The content uniformity was tested according to Test 1. The results are as follows:

[0151] batch number Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 1 93.06％ 103.87％ 102.23％ 101.14％ 2 105.40％ 101.87％ 102.50％ 102.77％ 3 108.48％ 98.67％ 100.08％ 98.92％ 4 101.21％ 95.81％ 98.44％ 98.04％ 5 98.31％ 99.64％ 97.07％ 100.73％ 6 106.65％ 98.46％ 99.14％ 97.02％ 7 107.08％ 102.93％ 98.04％ 99.48％ 8 104.75％ 100.62％ 98.73％ 97.40％ 9 100.27％ 98.69％ 98.48％ 100.56％ 10 106.79％ 101.34％ 102.29％ 101.61％ X bar 103.20％ 100.19％ 99.70％ 99.77％ RSD 4.7％ 2.4％ 2.0％ 1.9％

[0152] 2. Test according to test 2 (high temperature 40℃), the results are as follows:

[0153]

[0154] 3. Test the dissolution according to Test 3. The results are as follows: Figure 1 shown.

[0155] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A method for preparing granisetron hydrochloride tablets, characterized in that: The granisetron hydrochloride tablets are made from the following raw materials in parts by weight: The D 90 is 10 μm to 20 μm, and the D 50 10μm or more; The fillers are lactose and microcrystalline cellulose; The preparation method comprises the following steps: (1) crushing the granisetron hydrochloride raw material and mixing it with a portion of lactose to obtain a premix; the portion of lactose is 40% to 60% of the total mass of the lactose; (2) mixing the remaining lactose and other fillers with the obtained premix to obtain a mixture; (3) wet granulating the obtained mixture with a disintegrant and a binder solution to obtain an intermediate; (4) The obtained intermediate is mixed with a lubricant and tabletted.

2. The preparation method according to claim 1, characterized in that: The granisetron hydrochloride tablets are made from the following raw materials in parts by weight:

3. The preparation method according to claim 1, characterized in that: The granisetron hydrochloride tablets are made from the following raw materials in parts by weight:

4. The preparation method according to any one of claims 1 to 3, characterized in that: The granisetron hydrochloride is obtained by crushing the granisetron hydrochloride raw material through a 60-80 mesh sieve.

5. The preparation method according to any one of claims 1 to 3, characterized in that: The mass ratio of the microcrystalline cellulose to lactose is 1:1.1-4.

3.

6. The preparation method according to any one of claims 1 to 3, characterized in that: The mass ratio of the microcrystalline cellulose to lactose is 1:1.3-3.

8.

7. The preparation method according to any one of claims 1 to 3, characterized in that: The mass ratio of the microcrystalline cellulose to lactose is 1:1.5-3.

3.

8. The preparation method according to claim 1, characterized in that: The particle size of the lactose is less than 90 μm, and the particle size of the microcrystalline cellulose is 40 to 80 μm.

9. The preparation method according to any one of claims 1 to 3, characterized in that: The disintegrant is any one or more combinations of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethyl cellulose.

10. The preparation method according to any one of claims 1 to 3, characterized in that: The binder is any one or more combinations of hydroxypropyl cellulose, ethyl cellulose and hypromellose.

11. The preparation method according to any one of claims 1 to 3, characterized in that: The adhesive has a viscosity of 3 to 20 cPs.

12. The preparation method according to any one of claims 1 to 3, characterized in that: The lubricant is any one or more combinations of stearic acid, magnesium stearate and sodium stearyl fumarate.

13. The preparation method according to any one of claims 1 to 3, characterized in that: The lubricant is a lubricant that passes through a 60-80 mesh sieve.

14. The preparation method according to claim 1, characterized in that: In step (1), the partial lactose is 45%-55% of the total mass of lactose.

15. The preparation method according to claim 1, characterized in that: In step (2), the premix is ​​sieved through a 30-mesh sieve in a granulator, the remaining lactose is added and sieved repeatedly for 2 to 5 times, and then the remaining fillers are added and sieved to obtain a mixture.

16. The preparation method according to claim 1, characterized in that: In step (3), the binder solution is an aqueous solution of a binder, and the solid content of the binder in the binder solution is 3% g / ml to 13% g / ml.

17. The preparation method according to claim 16, characterized in that: The solid content of the adhesive in the adhesive solution is 5% g / ml to 10% g / ml.

18. The preparation method according to claim 1, characterized in that: In step (3), the wet granulation is carried out in a wet granulator through premixing, soft material preparation, wet granulation, drying and dry granulation.

19. The preparation method according to claim 18, characterized in that: During the premixing, the stirring blade rotates at 90-120 rpm, and the chopping blade rotates at 800-1000 rpm; during the preparation of the soft material, the stirring blade rotates at 100-150 rpm, and the chopping blade rotates at 1000-1500 rpm, and the mixing time is more than 10 minutes; during the wet granulation, the mesh aperture is 3 mm; The sieve aperture during the dry granulation is 1 mm.

20. The preparation method according to claim 1, characterized in that: In step (4), the mixing is performed in a mixer for 1 to 3 times; the charging factor of the mixer is 45% to 70%; during mixing, the rotating speed of the mixer is 10 to 20 rpm; and the mixing time is 1 to 5 minutes.

21. The preparation method according to claim 1, characterized in that: In step (4), during the tableting process, the ambient humidity is controlled below 65%.

22. The preparation method according to claim 1, characterized in that: Also included are coating materials.

23. The preparation method according to claim 22, characterized in that: The coating material is a gastric soluble film coating premix.

24. The preparation method according to claim 1, characterized in that: The plain tablets obtained after tablet compression are coated with coating materials to increase the weight by 2.0% to 5.0%; after coating, polyvinyl chloride / polyvinylidene chloride solid medicinal composite hard tablets and medicinal aluminum foil are used for packaging.

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