CN113842364B

CN113842364B - Oral solid preparation and preparation method thereof

Info

Publication number: CN113842364B
Application number: CN202111376516.2A
Authority: CN
Inventors: 高保安; 褚襄萍; 王刚; 焦金红; 刘金丹; 郝亚飞; 陈勇; 余贝欣; 陈仕魁; 毛昌元; 刘涛
Original assignee: Fujian Ruitailai Pharmaceutical Technology Co ltd
Current assignee: Fujian Ruitailai Pharmaceutical Technology Co ltd
Priority date: 2021-11-19
Filing date: 2021-11-19
Publication date: 2023-07-07
Anticipated expiration: 2041-11-19
Also published as: CN113842364A

Abstract

The invention relates to the technical field of medicines, in particular to an oral solid preparation and a preparation method thereof. Which comprises the following steps: the raw material medicines are subjected to independent wet granulation to prepare an oral solid preparation; the raw material medicine comprises one or more than two of clarithromycin, clopidogrel bisulfate, acetaminophen, aspirin, caffeine, desmethylvenlafaxine succinate and nifedipine. Compared with the prior art, the invention can overcome the sticking problem of the solid preparation caused by the characteristics of the raw material medicine, and ensure the smoothness of production.

Description

Oral solid preparation and preparation method thereof

Technical Field

The invention relates to the technical field of medicines, in particular to an oral solid preparation and a preparation method thereof.

Background

Common oral solid preparations include tablets, granules, capsules, dripping pills and the like, wherein the proportion of the oral solid preparations in the pharmaceutical preparations is more than 70%, and the tablets are the most common. The oral solid preparation has the characteristics of good stability, low production and manufacturing cost, convenient administration and carrying and good compliance of clinical medication. The essential procedure of the tablet preparation process is a tabletting procedure, the procedure is a core procedure of tablet production, and the most commonly encountered technical difficulty is sticking and punching, so that qualified products cannot be produced. Typically, the sticking is caused by a drug substance such as clarithromycin, clopidogrel bisulfate, acetaminophen, aspirin, caffeine, desvenlafaxine succinate, nifedipine, and the like.

Desmethylvenlafaxine succinate (desvenlafaxine succinate) is a 5-hydroxytryptamine-norepinephrine reuptake inhibitor, is a major active metabolite of venlafaxine, and has remarkable curative effect in clinic for treating Major Depressive Disorder (MDD). Chemical name: 4- (2- (dimethylamino) -1- (1-hydroxycyclohexyl) ethyl) phenol succinate monohydrate of formula: c16h25no2.c4h6o4.h2o, molecular weight: 399.48. sustained release tablet of desmethylvenlafaxine succinate manufactured by Wyethphasinc, U.S. under the trade name:

the Chinese medicine is approved to be marketed by the FDA in the United states in the year 2 and the month 29 in 2008, and is not marketed at present.

Depression is a type of mood disorder disease characterized by significant and persistent mood swings, one of the most common mental disorders, severely affecting the learning, life and social functions of the patient, and if not treated in a timely, effective, standardized manner, would result in a significant socioeconomic burden. Fei Lipeng et al show epidemiological investigation data of the city of four provinces of China: the month prevalence of mood disorders was 6.1% with depression 2.06%, but the therapeutic rate was less than 10%. According to the data statistics of the IQVIA sample hospital, the integral sales of the antidepressant in 2016-2018 is 41.8 hundred million yuan, the sales of venlafaxine products are 5 first, and the sales of the antidepressant products 10 first account for about 94.4% of the integral market, so that the research and development of the antidepressant pharmaceutical preparation is one of research hotspots of vast scientific researchers, and the clinical significance is great.

The sustained release tablet of the desmethylvenlafaxine succinate produced by Wyethphasinc company in the U.S. is described in the specification, and the product composition comprises the desmethylvenlafaxine succinate, the hypromellose, the microcrystalline cellulose, the talcum powder, the magnesium stearate and the gastric-soluble film coating powder, and the prescription dosage and the preparation process are not described in the specification. Original-ground (Hui's company) patent CN02808112.9 describes in example 15 a preparation method of "dry-mixing desmethylvenlafaxine succinate, hypromellose, microcrystalline cellulose, talc in a granulating pan, granulating with purified water as binder, drying, and then adding hypromellose and talc for mixing; finally adding magnesium stearate for total mixing and tabletting; the original patent WO2009075677A1 describes a prescription process wherein the prescription is "granule fraction: 75.87mg of desvenlafaxine succinate, 28.71mg of microcrystalline cellulose, 200.66mg of hypromellose, 5.83mg of talcum powder and 1.07mg of magnesium stearate, plus the powder fraction: the preparation method comprises the steps of mixing the raw materials of the granule part, granulating the mixture by a dry method, mixing the dry granule with the added powder, tabletting and coating, wherein 22.3mg of hydroxypropyl methylcellulose, 5.35mg of talcum powder, 3.21mg of magnesium stearate and 13.73mg of opadry II coating powder. According to the prescription process recorded in the original research patent, the inventor discovers that serious sticking and punching problems occur in the process of preparing tablets, and materials adhere to the surfaces of upper punch and lower punch, so that tablets are incomplete, qualified products cannot be smoothly produced, and particularly the sticking and punching problems are serious in the process of industrialized production. The inventor adopts a plurality of conventional means, such as increasing the dosage of anti-sticking agent magnesium stearate, increasing the dosage of lubricant talcum powder, changing the prescription proportion, controlling the moisture, adopting conventional granulation means and the like, which can not solve the sticking problem, and the technical problem seriously hinders the research and development process of the desmethylvenlafaxine succinate.

Disclosure of Invention

First, the technical problem to be solved

In view of the above-mentioned shortcomings and disadvantages of the prior art, the invention provides a preparation method of an oral solid preparation, which solves the technical problems of viscosity and the like caused by excessive viscosity of raw materials in the process of preparing the oral preparation from the raw materials.

Aiming at the problems of the medicines, the invention provides an oral solid preparation.

(II) technical scheme

In order to achieve the above purpose, the main technical scheme adopted by the invention comprises the following steps:

in a first aspect, an embodiment of the present invention provides a method for preparing an oral solid preparation, which includes the steps of: the raw material medicines are subjected to independent wet granulation to prepare an oral solid preparation;

in an alternative to the method of preparing the oral solid formulation of the present invention, wet granulation comprises: the wet granulation comprises: the raw materials are granulated by adding water for 30 to 600 seconds at the rotation speed of a stirring paddle of 100 to 500 revolutions per minute and the rotation speed of a cutting knife of 1000 to 2500 revolutions per minute, dried at the temperature of 70 to 80 ℃ and dried and granulated, and the obtained drug particles are prepared into oral solid preparations.

Wherein, the medicine particles are obtained by dry granulation by using a net with the aperture of 0.8-1.5 mm.

In an alternative to the method of preparing an oral solid formulation of the invention, it further comprises the steps of: and (3) carrying out dry granulation on the drug particles obtained by single wet granulation and the first auxiliary material to obtain the oral solid preparation.

In an alternative to the method of preparing the oral solid preparation of the present invention, dry granulation comprises: mixing the drug particles with the first auxiliary material, and then adding magnesium stearate to obtain a premix; and granulating the premixed material in a dry granulator to obtain dry granules.

Specifically, mixing the drug particles and the first auxiliary material for 10-45 minutes at the rotating speed of 10-20 r/min, adding magnesium stearate, and mixing for 5-15 minutes to obtain a premix; the premixed material is placed in a dry granulating machine, the pressure is set to be 60-150 bar, the gap between the pressing wheels is 1-2mm, the initial displacement is 0.5mm, the thickness of the ribbon is controlled to be 1-3 mm, the aperture of the whole grain screen is 1.0-1.5 mm, and dry granules are obtained through granulating.

In an alternative to the method of preparing an oral solid formulation of the invention, it further comprises the steps of: and (3) mixing the dry granules obtained by dry granulation with a second auxiliary material, tabletting or coating.

Optionally, the coating is a gastric soluble type Opadry coating, and the mass percentage of the coating in the solid preparation is 3-5%.

In an alternative scheme of the preparation method of the oral solid preparation, the first auxiliary material and the second auxiliary material are one or more than two of hydroxypropyl methylcellulose, microcrystalline cellulose, talcum powder, magnesium stearate and pharmaceutically acceptable excipients.

In an alternative to the method of preparing an oral solid formulation of the invention, the total mixing comprises: mixing the dry granules with the second auxiliary material for 10-45 minutes at the rotating speed of 10-20 rpm, adding magnesium stearate, and mixing for 5-15 minutes.

In an alternative to the method of preparation of the oral solid formulation of the invention, the coating is a gastric soluble type opadry coating.

In an alternative scheme of the preparation method of the oral solid preparation, the raw material medicine comprises one or more than two of clarithromycin, clopidogrel bisulfate, acetaminophen, aspirin, caffeine, desmethylvenlafaxine succinate and nifedipine.

The invention also provides an oral solid preparation prepared by the preparation method of the oral solid preparation in any scheme.

(III) beneficial effects

The beneficial effects of the invention are as follows: compared with the prior art, the preparation method of the oral solid preparation can overcome the sticking problem of the raw material medicine caused by the physical and chemical properties of the raw material medicine during the preparation of the solid preparation, and ensure the smoothness of production.

Detailed Description

The present invention will be described in detail below with reference to specific embodiments for better explaining the present invention.

The embodiment of the invention provides a preparation method of an oral solid preparation, which aims to overcome the sticking problem in the process of preparing a solid preparation from bulk drugs, and comprises the following steps: and (3) carrying out independent wet granulation on the raw materials to prepare the oral solid preparation.

The invention separately carries out wet granulation on the raw materials, effectively solves the sticking problem, and the pressed tablet is smooth, fine, glossy and clear in lettering.

Wherein the wet granulation specifically comprises: the raw materials are granulated by adding water for 30 to 600 seconds at the rotation speed of a stirring paddle of 100 to 500 revolutions per minute and the rotation speed of a cutting knife of 1000 to 2500 revolutions per minute, dried at the temperature of 70 to 80 ℃ and dried and granulated, and the obtained drug particles are prepared into oral solid preparations.

Preferably, the raw materials are granulated with water for 120-300 seconds at the rotation speed of a stirring paddle of 150-300 rpm and the rotation speed of a cutting knife of 1200-1800 rpm, dried at 70-80 ℃ and dried and granulated, and the obtained drug particles are prepared into oral solid preparations.

Wherein the weight ratio of the raw material medicine to the water is 14-18:1-4.

Wherein, the mesh with the aperture of 0.8-1.5mm is used for dry finishing, and the preferable aperture is 1.0-1.5 mm;

wherein the raw materials comprise one or more than two of clarithromycin, clopidogrel bisulfate, acetaminophen, aspirin, caffeine, desmethylvenlafaxine succinate and nifedipine. The raw material medicine is preferably a sustained release tablet of the desmethylvenlafaxine succinate.

The invention separately carries out wet granulation on the raw materials, can fundamentally solve the sticking problem, but has the content uniformity risk. In order to solve the problem of uniformity caused by wet granulation, the invention further adopts a dry granulation technology, and the drug particles obtained by the wet granulation and the first auxiliary materials are closely pressed and fixed together, so that the problem of uneven content can be solved, meanwhile, the fluidity of the materials is ensured, and the production is smoother, thereby ensuring the product quality, and the product quality is consistent with the original development agent, and has good uniformity and stability. The ingenious combination of the wet granulation technology and the dry granulation technology in the invention produces a remarkable substantial effect.

The dry granulation comprises the following steps: mixing the drug particles with the first auxiliary material, and then adding magnesium stearate to obtain a premix; and granulating the premixed material in a dry granulator to obtain dry granules.

Wherein, dry granules obtained by dry granulation are mixed with a second auxiliary material, and tabletting or coating can be carried out to prepare corresponding preparations.

The first auxiliary material and the second auxiliary material are preferably one or more than two of hypromellose, microcrystalline cellulose, talcum powder, magnesium stearate and pharmaceutically acceptable excipient.

The total mixing comprises: mixing the dry granules with the second auxiliary material for 10-45 minutes at the rotating speed of 10-20 rpm, adding magnesium stearate, and mixing for 5-15 minutes.

Tabletting is to put the total mixture into a tablet press, and punch the tablet with a square shape with a side length of 9mm to make the hardness 100-180N.

The coating is gastric soluble type Opadry coating.

Preferably, the drug particles of the present invention should have a particle size distribution of less than or equal to 40% of a fine powder of 80 mesh or less.

Preferably, the dry particles of the present invention should have a particle size distribution of less than or equal to 75% of a fine powder of 80 mesh or less.

In order to better understand the above technical solution, exemplary embodiments of the present invention will be described in more detail below. While exemplary embodiments of the invention are shown below, it should be understood that the invention may be embodied in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

Comparative example 1: feasibility verification of preparation method described in original patent CN02808112.9

The original patent CN02808112.9 describes in example 15 a preparation method of "dry mixing venlafaxine succinate, hypromellose, microcrystalline cellulose, talc in a granulator, granulating with purified water as binder, drying, and then adding hypromellose and talc for mixing; finally, adding magnesium stearate for total mixing and tabletting. Based on this, the present inventors have verified the feasibility of the preparation method described in this patent.

75.87g of desmethylvenlafaxine succinate, 200.66g of hydroxypropyl methylcellulose, 28.71g of microcrystalline cellulose and 5.83g of talcum powder are weighed and placed in a 2L wet granulation pot, a stirring paddle is started, the rotating speed is 300 revolutions per minute, a cutting knife is started, the rotating speed is 1800 revolutions per minute, and purified water is slowly added for granulation. The amount of purified water was gradually increased by 5%, 10% and 15% of the total amount of the materials, and the granulation state was observed, and the results are shown in the following table.

Granulation effect of the preparation method described in original patent CN02808112.9

As described above, according to the preparation method described in patent CN02808112.9, the fine powder of the particles and the pimple were differentiated from each other, and uniform particles could not be obtained. This may be related to the fact that hypromellose is very prone to absorb water and agglomerate, and the inventors of the present invention subsequently verify that the reduction of the proportion of hypromellose series does not have a fundamental improvement in the granulating effect, and no uniform particles can be obtained, which cannot be implemented industrially.

Comparative example 2: feasibility verification of preparation method described in original patent WO2009075677A1

The original patent WO2009075677A1, example 1, describes a prescription process wherein the prescription is "granule fraction: 75.87mg of desvenlafaxine succinate, 28.71mg of microcrystalline cellulose, 200.66mg of hypromellose, 5.83mg of talcum powder and 1.07mg of magnesium stearate, with the addition of powder fractions: the preparation method comprises the steps of mixing the raw materials of the granule part, granulating the mixture by a dry method, mixing the dry granule with the added powder, tabletting and coating, wherein 22.3mg of hydroxypropyl methylcellulose, 5.35mg of talcum powder, 3.21mg of magnesium stearate and 13.73mg of opadry II coating powder. Feasibility verification was performed according to the prescription procedure described in this patent.

15.17kg of desmethylvenlafaxine succinate, 40.13kg of hydroxypropyl methylcellulose, 5.74kg of microcrystalline cellulose and 1.17kg of talcum powder are weighed, placed in an 800L hopper mixer, mixed for 30 minutes at 10 revolutions per minute, added with 0.21kg of magnesium stearate, and mixed for 5 minutes at 10 revolutions per minute to obtain a premixed material; the premixed material is placed in a dry granulator, hydraulic pressure is set to be 80-100bar, a pinch roller gap is 1-2mm, the rotation speed of a press roller is 16rpm, the horizontal feeding speed is 40rpm, the vertical feeding speed is 10rpm, the initial displacement is 0.5mm, the material sucking speed is 5S, the discharging speed is 2S, the aperture of a primary sizing screen is 5.0mm, the rotation speed of the primary sizing screen is 60rpm, the aperture of a secondary screen is 1.2mm, and the rotation speed of the secondary sizing screen is 60rpm. The thickness of the measured ribbons is about 2mm, the proportion of fine powder below 80 meshes is about 45%, and the dry granulation effect is good, thus obtaining dry granules; weighing dry granules, placing the dry granules in an 800L hopper mixer, adding additional hypromellose and talcum powder according to the prescription proportion recorded in the patent, mixing for 30 minutes at 10rpm, adding magnesium stearate, and mixing for 5 minutes at 10rpm to obtain total mixed granules; the total mixed particles were placed in a tablet press and punched with a square of 9mm side to give tablets weighing approximately 343mg and hardness controlled between 100 and 180N. Experiments show that about 30 minutes of tabletting is carried out, obvious sticking and punching problems occur, the surface of the tablet is obviously missing, and the lettering is fuzzy, so that the production cannot be carried out. The inventor of the present invention subsequently makes a series of researches on the control of dry granulation parameters and subdivision rates, and can not fundamentally solve the sticking problem, thus seriously impeding the industrialized production. Therefore, the conventional preparation method described in WO2009075677A1 has the problem of sticking and punching, and cannot complete the industrialized production.

Comparative example 3: verification of feasibility of solving sticking problem by increasing magnesium stearate dosage

As known to those skilled in the art, magnesium stearate is the most commonly used efficient lubricant for solving the sticking problem of tablets, and has remarkable effect, so the inventors of the present invention respectively increase the magnesium stearate amount by 0.5%, 1% and 1.5% on the basis of comparative example 2, examine the influence on the sticking problem after increasing the magnesium stearate amount, and design and results of experiments are as follows.

1. Prescription of prescription

10kg of the total mixed particles prepared in comparative example 2 were weighed, 3 parts were weighed in parallel, and 0.5%, 1% and 1.5% of magnesium stearate of the total mixed particles were added respectively, and the formulation was designed as follows.

Composition of the composition	Prescription one	Prescription two	Prescription III
				Total mixed particles	10.12kg	10.00kg	10.05kg
Magnesium stearate	0.05kg	0.10kg	0.15kg

2. Process for producing a solid-state image sensor

Weighing total mixed particles with a prescription amount, placing the total mixed particles in a 50L hopper mixer, mixing for 30 minutes at 10 revolutions per minute, adding magnesium stearate, and mixing for 5 minutes at 10 revolutions per minute to obtain total mixed materials with different magnesium stearate contents; the total mixed granules were placed in a tablet press and punched with square punches having a side length of 9mm to give tablets weighing about 345mg, 346mg, 348mg, respectively.

3. Experimental results

The tabletting results show that the sticking problems with different degrees appear when the magnesium stearate dosage is increased by 0.5%, 1% and 1.5%, the surface of the tablet is obviously missing, the characters are blurred, and the sticking stroke degree and the sticking time are not regularly changed along with the increase of the magnesium stearate dosage. Therefore, magnesium stearate has poor effect on solving the sticking problem. The inventor also examines the dosage of the anti-adhesive talcum powder in the prescription, and the sticking problem can not be solved.

In summary, for the present product, the effect of solving the sticking problem according to the prior art is not good, so that the production cannot be completed.

Example 1: preparation of desmethylvenlafaxine succinate sustained-release tablet

1. Preparation of bulk drug particles

15.17kg of desmethylvenlafaxine succinate is weighed and placed in a 70L wet granulation pot, a stirring paddle is started, the rotating speed is 200 revolutions per minute, a cutting knife is started, the rotating speed is 1440 revolutions per minute, 1.97kg of purified water is slowly added, and granulation is carried out for 240 seconds, so that wet granules are obtained. The wet granules were placed in a fluidized bed and dried at 80℃with a moisture content of 2.44% to give dry granules. And (5) carrying out dry granulation on the dry granules by using a net with the aperture of 1.5mm to obtain the medicine granules. The detection shows that the fine powder rate below 80 meshes is 35.3 percent.

2. Dry granulation

14.01kg of medicine particles, 37.07kg of hydroxypropyl methylcellulose, 5.31kg of microcrystalline cellulose and 1.08kg of talcum powder are weighed and placed in an 800L hopper mixer, mixed for 30 minutes at the rotating speed of 10 revolutions per minute, added with 0.20kg of magnesium stearate and mixed for 5 minutes to obtain a premixed material. Placing the premixed material into a dry granulating machine, setting hydraulic pressure to be 80-100bar, a pinch roller clearance to be 1-2mm, a press roller rotating speed to be 16rpm, a horizontal feeding speed to be 40rpm, a vertical feeding speed to be 10rpm, an initial displacement to be 0.5mm, a suction speed to be 5S, a discharge speed to be 2S, a primary granule finishing screen aperture to be 5.0mm, a primary granule finishing rotating speed to be 60rpm, a secondary screen aperture to be 1.2mm and a secondary granule finishing rotating speed to be 60rpm, and performing dry granulation to obtain dry granules. Through inspection, the thickness of the measured ribbons is 1.9-2.3mm, and the proportion of fine powder below 80 meshes is 51%.

3. General mixing

55.12kg of dry granules, 10.00kg of hypromellose and 0.94kg of talcum powder are weighed and placed in an 800L hopper mixer, the rotating speed is 10 revolutions per minute, the mixture is mixed for 20 minutes, 0.57kg of magnesium stearate is added, and the mixture is mixed for 5 minutes, so that the total mixed material is obtained.

4. Tabletting

The total mixture is placed in a tablet press, and is punched into tablets by a square with the side length of 9mm, so that the tablet weight is about 377mg, and the desmethylvenlafaxine succinate sustained-release tablet is obtained. The tabletting result shows that the sticking phenomenon is not seen, the tablet surface is complete, the characters are clearly carved, and the hardness is 120-160N.

5. Coating layer

The sustained release tablet of the desmethylvenlafaxine succinate is placed in a coating pot, the air inlet temperature is set to be 70 ℃, and the air outlet temperature is controlled to be 50-55 ℃. And (3) weighing the gastric-soluble Ophio coating premixed powder, slowly adding the gastric-soluble Ophio coating premixed powder into purified water in a stirring state to ensure that the solid content is 15%, and performing film coating according to law. The weight of the coating is increased by 3.28 percent, the water content is 2.66 percent, and the desmethylvenlafaxine succinate sustained release tablet is obtained.

According to the preparation process, tabletting is smooth, sticking and punching phenomena are not seen, the surface of the tablet is complete, and the lettering is clear. Further embodying the superiority of the technical proposal of the invention.

Example 2: preparation of desmethylvenlafaxine succinate sustained-release tablet

1. Preparation of bulk drug particles

15.17kg of desmethylvenlafaxine succinate is weighed and placed in a 70L wet granulation pot, a stirring paddle is started, the rotating speed is 100 rpm, a cutting knife is started, the rotating speed is 1000 rpm, 3.03kg of purified water is slowly added, and granulation is carried out for 30 seconds, so that wet granules are obtained. The wet granules were placed in a fluidized bed and dried at 80℃with a moisture of 2.04% to give dry granules. And (5) carrying out dry granulation on the dry granules by using a net with the aperture of 1.5mm to obtain the medicine granules. The detection shows that the fine powder rate below 80 meshes is 12.6 percent.

2. Dry granulation

14.52kg of medicine particles, 38.42kg of hydroxypropyl methylcellulose, 5.50kg of microcrystalline cellulose and 1.12kg of talcum powder are weighed and placed in an 800L hopper mixer, the rotating speed is 20 revolutions per minute, the mixture is mixed for 45 minutes, 0.20kg of magnesium stearate is added, and the mixture is mixed for 15 minutes, so that the premixed material is obtained. Placing the premixed material into a dry granulating machine, setting hydraulic pressure to 120-150bar, a pinch roller clearance to 1-2mm, a press roller rotating speed to 16rpm, a horizontal feeding speed to 30rpm, a vertical feeding speed to 10rpm, an initial displacement to 0.5mm, a suction speed to 5S, a discharge speed to 2S, a primary granule finishing screen aperture to 1.0mm, a primary granule finishing rotating speed to 60rpm, a secondary screen aperture to 1.2mm, and a secondary granule finishing rotating speed to 60rpm, and performing dry granulation to obtain dry granules. Through inspection, the thickness of the ribbon is measured to be 1.0-1.3mm, and the proportion of fine powder below 80 meshes is 36%.

3. General mixing

57.33kg of dry granules, 10.40kg of hypromellose and 0.98kg of talcum powder are weighed and placed in an 800L hopper mixer, the rotating speed is 10 revolutions per minute, the mixture is mixed for 20 minutes, 0.59kg of magnesium stearate is added, and the mixture is mixed for 5 minutes, so that the total mixed material is obtained.

4. Tabletting

The total mixture is placed in a tablet press, and is punched into tablets by a square with the side length of 9mm, so that the tablet weight is about 377mg, and the desmethylvenlafaxine succinate sustained-release tablet is obtained. The tabletting result shows that the sticking phenomenon is not seen, the tablet surface is complete, the characters are clearly carved, and the hardness is between 153 and 180N.

5. Coating layer

The sustained release tablet of the desmethylvenlafaxine succinate is placed in a coating pot, the air inlet temperature is set to be 70 ℃, and the air outlet temperature is controlled to be 50-55 ℃. And (3) weighing the gastric-soluble Ophio coating premixed powder, slowly adding the gastric-soluble Ophio coating premixed powder into purified water in a stirring state, and coating by a film after the solid content is 15%. The weight gain of the coating is 4.78%, the water content is 2.56%, and the desmethylvenlafaxine succinate sustained release tablet is obtained.

Example 3: preparation of desmethylvenlafaxine succinate sustained-release tablet

1. Preparation of bulk drug particles

17kg of desvenlafaxine succinate is weighed and placed in a 70L wet granulation pot, a stirring paddle is started, the rotating speed is 500 rpm, a cutting knife is started, the rotating speed is 2500 rpm, 0.76kg of purified water is slowly added, and granulation is carried out for 600 seconds, so that wet granules are obtained. The wet granules were placed in a fluidized bed and dried at 80℃with a moisture content of 2.61% to give dry granules. And (5) carrying out dry granulation on the dry granules by using a net with the aperture of 0.8mm to obtain the medicine granules. The detection shows that the fine powder rate below 80 meshes is 39.5%.

2. Dry granulation

14.33kg of medicine particles, 37.91kg of hydroxypropyl methylcellulose, 5.43kg of microcrystalline cellulose and 1.10kg of talcum powder are weighed and placed in an 800L hopper mixer, mixed for 10 minutes at the rotating speed of 10 revolutions per minute, added with 0.20kg of magnesium stearate and mixed for 5 minutes to obtain a premixed material. Placing the premixed material into a dry granulating machine, setting hydraulic pressure to be 60-90bar, a pinch roller clearance to be 1-2mm, a press roller rotating speed to be 10rpm, a horizontal feeding speed to be 20rpm, a vertical feeding speed to be 10rpm, an initial displacement to be 0.5mm, a suction speed to be 5S, a discharge speed to be 2S, a primary granule finishing screen aperture to be 1.0mm, a primary granule finishing rotating speed to be 60rpm, a secondary screen aperture to be 1.0mm and a secondary granule finishing rotating speed to be 60rpm, and performing dry granulation to obtain dry granules. Through inspection, the thickness of the measured ribbons is 1.5-1.7mm, and the proportion of fine powder below 80 meshes is 35.2%.

3. General mixing

Weighing 56.24kg of dry granules, 10.20kg of hypromellose and 0.96kg of talcum powder, placing into an 800L hopper mixer, mixing at a rotating speed of 20rpm for 45 minutes, adding 0.58kg of magnesium stearate, and mixing for 5 minutes to obtain a total mixed material.

4. Tabletting

The total mixture is placed in a tablet press, and is punched into tablets by a square with the side length of 9mm, so that the tablet weight is about 377mg, and the desmethylvenlafaxine succinate sustained-release tablet is obtained. The tabletting result shows that no sticking and punching phenomenon is seen, the tablet surface is complete, the characters are clearly carved, and the hardness is 102-145N.

5. Coating layer

The sustained release tablet of the desmethylvenlafaxine succinate is placed in a coating pot, the air inlet temperature is set to be 65 ℃, and the air outlet temperature is controlled to be 45-50 ℃. And (3) weighing the gastric-soluble Ophio coating premixed powder, slowly adding the gastric-soluble Ophio coating premixed powder into purified water in a stirring state to ensure that the solid content is 15%, and performing film coating according to law. Coating weight gain is 3.2%, and water content is 2.7%, thus obtaining the desmethylvenlafaxine succinate sustained release tablet.

Example 4: preparation of desmethylvenlafaxine succinate sustained-release tablet

1. Preparation of bulk drug particles

Weighing 16kg of desmethylvenlafaxine succinate, placing in a 70L wet granulation kettle, starting a stirring paddle at a rotation speed of 350 rpm, starting a cutting knife at a rotation speed of 1800 rpm, slowly adding 1.82kg of purified water, and granulating for 300 seconds to obtain wet granules. The wet granules were placed in a fluidized bed and dried at 70 c with a moisture of 2.67% to obtain dry granules. And (5) carrying out dry granulation on the dry granules by using a net with the aperture of 1.2mm to obtain the medicine granules. The detection shows that the fine powder rate below 80 meshes is 31.4 percent.

2. Dry granulation

14.29kg of medicine particles, 37.81kg of hydroxypropyl methylcellulose, 5.41kg of microcrystalline cellulose and 1.10kg of talcum powder are weighed and placed in an 800L hopper mixer, the rotating speed is 15 revolutions per minute, the mixture is mixed for 20 minutes, 0.20kg of magnesium stearate is added, and the mixture is mixed for 8 minutes, so that the premixed material is obtained. Placing the premixed material into a dry granulating machine, setting hydraulic pressure to be 80-100bar, a pinch roller clearance to be 1-2mm, a press roller rotating speed to be 20rpm, a horizontal feeding speed to be 60rpm, a vertical feeding speed to be 10rpm, an initial displacement to be 0.5mm, a suction speed to be 10S, a discharging speed to be 2S, a primary granule finishing screen aperture to be 1.5mm, a primary granule finishing rotating speed to be 60rpm, a secondary screen aperture to be 1.0mm and a secondary granule finishing rotating speed to be 60rpm, and performing dry granulation to obtain dry granules. Through inspection, the thickness of the measured ribbons is 2.5-2.7mm, and the proportion of fine powder below 80 meshes is 64.6%.

3. General mixing

Weighing 55.36kg of dry granules, 10.04kg of hypromellose and 0.95kg of talcum powder, placing into an 800L hopper mixer, mixing at a rotating speed of 20rpm for 45 minutes, adding 0.57kg of magnesium stearate, and mixing for 5 minutes to obtain a total mixed material.

4. Tabletting

The total mixture is placed in a tablet press, and is punched into tablets by a square with the side length of 9mm, so that the tablet weight is about 377mg, and the desmethylvenlafaxine succinate sustained-release tablet is obtained. The tabletting result shows that no sticking and punching phenomenon is seen, the tablet surface is complete, the characters are clearly carved, and the hardness is between 133 and 167N.

5. Coating layer

The sustained release tablet of the desmethylvenlafaxine succinate is placed in a coating pot, the air inlet temperature is set to be 60 ℃, and the air outlet temperature is controlled to be 40-45 ℃. And (3) weighing the gastric-soluble Ophio coating premixed powder, slowly adding the gastric-soluble Ophio coating premixed powder into purified water in a stirring state to ensure that the solid content is 15%, and performing film coating according to law. The weight gain of the coating is 2.87 percent, the water content is 3.54 percent, and the desmethylvenlafaxine succinate sustained release tablet is obtained.

Example 5: preparation of desmethylvenlafaxine succinate sustained-release tablet

1. Preparation of bulk drug particles

15kg of desmethylvenlafaxine succinate is weighed and placed in a 70L wet granulation pot, a stirring paddle is started, the rotating speed is 300 revolutions per minute, a cutting knife is started, the rotating speed is 1500 revolutions per minute, 2.28kg of purified water is slowly added, and granulation is carried out for 120 seconds, so that wet granules are obtained. The wet granules were placed in an oven and dried at 60 c with a moisture of 1.98% to give dry granules. And (5) carrying out dry granulation on the dry granules by using a net with the aperture of 1.5mm to obtain the medicine granules. The detection shows that the fine powder rate below 80 meshes is 24.5%.

2. Dry granulation

14.72kg of medicine particles, 38.95kg of hydroxypropyl methylcellulose, 5.58kg of microcrystalline cellulose and 1.13kg of talcum powder are weighed and placed in an 800L hopper mixer, the rotating speed is 15 revolutions per minute, the mixture is mixed for 40 minutes, 0.21kg of magnesium stearate is added, and the mixture is mixed for 10 minutes, so that the premixed material is obtained. Placing the premixed material into a dry granulating machine, setting a hydraulic pressure of 110-140bar, a pinch roller clearance of 1-2mm, a press roller rotating speed of 20rpm, a horizontal feeding speed of 50rpm, a vertical feeding speed of 15rpm, an initial displacement of 0.5mm, a suction speed of 10S, a discharge speed of 3S, a primary granule finishing screen aperture of 1.2mm, a primary granule finishing rotating speed of 60rpm, a secondary screen aperture of 1.2mm and a secondary granule finishing rotating speed of 60rpm, and performing dry granulation to obtain dry granules. Through inspection, the thickness of the ribbons is measured to be 1.9-2.3mm, and the proportion of fine powder below 80 meshes is 55.9%.

3. General mixing

57.43kg of dry granules, 10.41kg of hypromellose and 0.98kg of talcum powder are weighed and placed in an 800L hopper mixer, the rotating speed is 10 revolutions per minute, the mixture is mixed for 20 minutes, 0.59kg of magnesium stearate is added, and the mixture is mixed for 5 minutes, so that the total mixed material is obtained.

4. Tabletting

The total mixture is placed in a tablet press, and is punched into tablets by a square with the side length of 9mm, so that the tablet weight is about 377mg, and the desmethylvenlafaxine succinate sustained-release tablet is obtained. The tabletting result shows that the sticking phenomenon is not seen, the tablet surface is complete, the characters are clearly carved, and the hardness is 114-147N.

5. Coating layer

The sustained release tablet of the desmethylvenlafaxine succinate is placed in a coating pot, the air inlet temperature is set to be 75 ℃, and the air outlet temperature is controlled to be 50-55 ℃. And (3) weighing the gastric-soluble Ophio coating premixed powder, slowly adding the gastric-soluble Ophio coating premixed powder into purified water in a stirring state to ensure that the solid content is 15%, and performing film coating according to law. The weight gain of the coating is 3.08 percent, the water content is 2.35 percent, and the desmethylvenlafaxine succinate sustained release tablet is obtained.

Example 6: preparation of desmethylvenlafaxine succinate sustained-release tablet

1. Preparation of bulk drug particles

18kg of desmethylvenlafaxine succinate is weighed and placed in a 70L wet granulation pot, a stirring paddle is started, the rotating speed is 200 revolutions per minute, a cutting knife is started, the rotating speed is 1440 revolutions per minute, 1.97kg of purified water is slowly added, and granulation is carried out for 240 seconds, so that wet granules are obtained. The wet granules were placed in an oven and dried at 50 c with a moisture of 2.71% to give dry granules. And (5) carrying out dry granulation on the dry granules by using a net with the aperture of 1.5mm to obtain the medicine granules. The detection shows that the fine powder rate below 80 meshes is 27.3 percent.

2. Dry granulation

14.55kg of medicine particles, 38.50kg of hydroxypropyl methylcellulose, 5.51kg of microcrystalline cellulose and 1.12kg of talcum powder are weighed and placed in an 800L hopper mixer, the rotating speed is 15 revolutions per minute, the mixture is mixed for 40 minutes, 0.21kg of magnesium stearate is added, and the mixture is mixed for 10 minutes, so that the premixed material is obtained. Placing the premixed material into a dry granulating machine, setting a hydraulic pressure of 110-140bar, a pinch roller clearance of 1-2mm, a press roller rotating speed of 16rpm, a horizontal feeding speed of 35rpm, a vertical feeding speed of 15rpm, an initial displacement of 0.5mm, a suction speed of 8S, a discharge speed of 2S, a primary granule finishing screen aperture of 1.2mm, a primary granule finishing rotating speed of 60rpm, a secondary screen aperture of 1.2mm and a secondary granule finishing rotating speed of 60rpm, and performing dry granulation to obtain dry granules. Through inspection, the thickness range of the measured ribbons is 1.8-2.2mm, and the proportion of fine powder below 80 meshes is 55.1%.

3. General mixing

Weighing 56.82kg of dry granules, 10.30kg of hypromellose and 0.97kg of talcum powder, placing into an 800L hopper mixer, mixing at a rotating speed of 10rpm for 20 minutes, adding 0.58kg of magnesium stearate, and mixing for 5 minutes to obtain a total mixed material.

4. Tabletting

The total mixture is placed in a tablet press, and is punched into tablets by a square with the side length of 9mm, so that the tablet weight is about 377mg, and the desmethylvenlafaxine succinate sustained-release tablet is obtained. The tabletting result shows that no sticking and punching phenomenon is seen, the tablet surface is complete, the characters are clearly carved, and the hardness is 146-175N.

5. Coating layer

The sustained release tablet of the desmethylvenlafaxine succinate is placed in a coating pot, the air inlet temperature is set to be 75 ℃, and the air outlet temperature is controlled to be 50-55 ℃. And (3) weighing the gastric-soluble Ophio coating premixed powder, slowly adding the gastric-soluble Ophio coating premixed powder into purified water in a stirring state to ensure that the solid content is 15%, and performing film coating according to law. The weight of the coating is increased by 3.43 percent, the water content is 2.77 percent, and the desmethylvenlafaxine succinate sustained release tablet is obtained.

Example 7: preparation of clarithromycin sustained release tablets

1. Preparation of bulk drug particles

10kg of clarithromycin is weighed and placed in a 70L wet granulation pot, a stirring paddle is started, the rotating speed is 250 revolutions per minute, a cutting knife is started, the rotating speed is 2000 revolutions per minute, 1.5kg of purified water is slowly added, and granulation is carried out for 180 seconds, so that wet granules are obtained. The wet granules are placed in a fluidized bed and dried at 60 ℃ to obtain dry granules, wherein the moisture is 1.98 percent. And (5) carrying out dry granulation on the dry granules by using a net with the aperture of 1.2mm to obtain the medicine granules. The detection shows that the fine powder rate below 80 meshes is 24.4%.

2. Dry granulation

9.5kg of medicine particles, 10.5kg of hydroxypropyl methylcellulose, 2.2kg of microcrystalline cellulose and 0.82kg of talcum powder are weighed and placed in an 800L hopper mixer, the rotating speed is 15 revolutions per minute, the mixture is mixed for 20 minutes, 0.21kg of magnesium stearate is added, and the mixture is mixed for 5 minutes, so that the premixed material is obtained. Placing the premixed material into a dry granulating machine, setting hydraulic pressure to be 100-120bar, a pinch roller clearance to be 1-2mm, a press roller rotating speed to be 15rpm, a horizontal feeding speed to be 25rpm, a vertical feeding speed to be 12rpm, an initial displacement to be 0.5mm, a suction speed to be 5S, a discharge speed to be 3S, a primary granule finishing screen aperture to be 5mm, a primary granule finishing rotating speed to be 60rpm, a secondary screen aperture to be 1.5mm and a secondary granule finishing rotating speed to be 60rpm, and performing dry granulation to obtain dry granules. Through inspection, the thickness of the ribbons is measured to be 1.6-2.0mm, and the proportion of fine powder below 80 meshes is 38.3%.

3. General mixing

21.83kg of dry granules, 3.21kg of hypromellose and 0.36kg of talcum powder are weighed and placed in a 100L hopper mixer, the rotating speed is 15 revolutions per minute, the mixture is mixed for 20 minutes, 0.28kg of magnesium stearate is added, and the mixture is mixed for 5 minutes, so that the total mixed material is obtained.

4. Tabletting

The total mixture is placed into a tablet press, and is pressed into tablets by a round punching with the side length of 11mm, so that the tablet weight is about 575mg, and the clarithromycin slow-release tablet is obtained. The tabletting result shows that no sticking phenomenon is seen, the tablet surface is smooth and glossy, and the hardness is 155-189N.

5. Coating layer

The clarithromycin sustained-release tablets are placed in a coating pot, the air inlet temperature is set to be 55 ℃, and the air outlet temperature is controlled to be 40-45 ℃. And (3) weighing the gastric-soluble Ophio coating premixed powder, slowly adding the gastric-soluble Ophio coating premixed powder into purified water in a stirring state to ensure that the solid content is 15%, and performing film coating according to law. The weight of the coating is increased by 4.01 percent, the water content is 2.33 percent, and the clarithromycin sustained release tablet is obtained.

Test example 1: comparison of in vitro dissolution of the formulations of the invention with commercially available original development agents

The sustained release tablet of the desmethylvenlafaxine succinate (sample of example 1) produced by the preparation method of the invention is used as a preparation of the invention, the sustained release tablet of the desmethylvenlafaxine succinate produced by Wyethphasinc company in U.S. is used as a reference preparation, 900ml of 0.9% sodium chloride solution is used as a dissolution medium, the operation is carried out according to a dissolution rate and release rate measuring method (the first method of the fourth rule 0931 of the Chinese pharmacopoeia 2020 edition) for 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 20 hours and 24 hours, a proper amount of solution is respectively taken, the measurement is carried out according to a high performance liquid chromatography (the fourth rule 0512 of the Chinese pharmacopoeia 2020 edition), the concentration of the desmethylvenlafaxine is calculated according to an external standard method by using the peak area, and the dissolution rate of each tablet is calculated.

The in vitro dissolution rate of the preparation of the invention and the commercial original development agent is determined as follows:

in vitro dissolution rate measurement result of preparation of the invention and commercial original development agent

Analysis of results:

the dissolution rate of the prepared sustained release tablet of the desmethylvenlafaxine succinate in vitro is equivalent to that of the original preparation, and the dissolution curve similarity factor f2 is up to 84.4.

Test example 2: the content uniformity of the desmethylvenlafaxine succinate sustained release tablet is measured

Taking 10 tablets of the invention in examples 1-7, and measuring according to high performance liquid chromatography (four general rules 0512 in China pharmacopoeia 2020). The uniformity of content measured by the method under the proposed content measurement item should meet the rule (the fourth rule 0941 of the year 2020 edition of Chinese pharmacopoeia), namely A+2.2S should be less than 15. The content uniformity was measured as follows.

Determination of the uniformity of the content of the tablets prepared in examples 1 to 7 of the present invention

Number of sheets	Example 1	Example 2	Example 3	Example 4	Example 5	Example 6	Example 7
								A+2.2S	2.7	2.5	1.9	3.0	4.5	2.9	4.1

Analysis of results:

according to the preparation method of the invention, the content uniformity of the tablets prepared in examples 1-7 meets the requirement, and the uniformity is good.

The invention granulates the raw materials by wet method, solves the sticking problem ingeniously, ensures the feasibility of the production process, and the product quality is not inferior to that of the original grinding preparation. The method provides a new solution for preparing tablets of raw materials such as clarithromycin, clopidogrel bisulfate, acetaminophen, aspirin, caffeine, desmethylvenlafaxine succinate, nifedipine and the like which are easy to cause sticking.

Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.

Claims

1. A method for preparing an oral solid preparation, comprising the steps of: the preparation method comprises the steps of performing independent wet granulation on raw material medicines, performing dry granulation on medicine particles obtained through independent wet granulation and a first auxiliary material to obtain an oral solid preparation, mixing dry granules obtained through dry granulation with a second auxiliary material, tabletting or coating to obtain the oral solid preparation;

the bulk drug is desmethylvenlafaxine succinate.

2. The method of preparing an oral solid formulation according to claim 1, wherein the wet granulation comprises: the raw materials are granulated by adding water for 30 to 600 seconds at the rotation speed of a stirring paddle of 100 to 500 revolutions per minute and the rotation speed of a cutting knife of 1000 to 2500 revolutions per minute, dried at the temperature of 70 to 80 ℃ and dried and granulated, and the obtained drug particles are prepared into oral solid preparations.

3. The method for preparing an oral solid preparation according to claim 1, wherein the dry granulation comprises: mixing the drug particles with the first auxiliary material, and then adding magnesium stearate to obtain a premix; and granulating the premixed material in a dry granulator to obtain dry granules.

4. The method for preparing an oral solid preparation according to claim 1, wherein: the first auxiliary material and the second auxiliary material are one or a combination of more than two of hypromellose, microcrystalline cellulose, talcum powder, magnesium stearate and pharmaceutically acceptable excipient.

5. The method for preparing an oral solid preparation according to claim 1, wherein: the total mixing comprises: mixing the dry granules with the second auxiliary material for 10-45 minutes at the rotating speed of 10-20 rpm, adding magnesium stearate, and mixing for 5-15 minutes.

6. The method for preparing an oral solid preparation according to claim 1, wherein: the coating is a gastric soluble type Opadry coating.

7. An oral solid preparation produced by the method for producing an oral solid preparation according to any one of claims 1 to 6.