Mesalazine soft material, mesalazine tablet and preparation method thereof

Abstract

The invention provides a mesalazine soft material, mesalazine tablets and a preparation method thereof. The preparation method of the soft material comprises the following steps: providing the active component, wherein the bulk density of the active component is 0.27-0.35 g / mL; dry-mixing the active component with povidone, sodium carboxymethyl starch and hydroxypropyl methylcellulose to obtain a basic granulation dry material; adding water into the basic granulation dry material, stirring and shearing to obtain a soft material; wherein the active component is mesalazine or a pharmaceutically acceptable salt thereof; the weight of the water is 38-42% of the weight of the basic granulation dry material; the rotating speed of a stirring paddle used for stirring and shearing is 80-120rpm; the rotating speed of the cutter is 900 to 1500 rpm (revolutions per minute); the stirring and shearing time is 5-7 minutes. According to the preparation method of the soft material, the end point of wet granulation can be clearly and easily achieved, the soft material with excellent properties is obtained, and a good foundation is laid for subsequent production processes and detection release of products.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a mesalazine soft material, a mesalazine tablet and a preparation method thereof. Background Art

[0002] Wet granulation is most widely used in the pharmaceutical industry because of its mature production technology, high production efficiency, good particle quality, beautiful appearance, strong wear resistance, and good compression molding.

[0003] However, in wet granulation, how to control the end point of wet granulation to obtain soft materials with excellent properties is only described in textbooks as "it forms a ball when held and falls apart when touched", and no clear method is given.

[0004] In order to obtain soft materials with excellent properties, in the commercial production process of drugs, production personnel usually use their hands to feel the state of the soft materials until the soft materials reach a state where they can be squeezed into lumps without being sticky, and can be broken apart by light pressure with fingers (the end point of wet granulation).

[0005] However, the combined effects of fluctuations in material properties such as particle size, particle shape and moisture content of raw and auxiliary materials between different batches, as well as slight changes in equipment performance / process operations, make it very difficult for production personnel to judge the endpoint of wet granulation, which can easily lead to over-granulation or under-granulation, making it difficult to proceed to the next step of granulation and tableting, resulting in many batches of production failures.

[0006] Among them, excessive granulation will cause the soft material to be too sticky, making granulation difficult, and may also lead to slow dissolution and release rate of the prepared sustained-release tablets, uneven drying of the boiling dryer, prolonged process time, difficult process control and increased costs. Insufficient granulation will cause the soft material to be weak in viscosity, poor granulation, and more fine powder. It may also lead to poor compressibility of the total mixture used for tableting, tablet adhesion, tablet cracking and other phenomena.

[0007] Mesalazine, also known as 5-aminosalicylic acid, is a drug used to treat ulcerative colitis and Crohn's disease. Mesalazine can inhibit the synthesis of prostaglandins that cause inflammation and the formation of inflammatory mediators leukotrienes, thereby significantly inhibiting inflammation of the intestinal mucosa, and has a better effect on the connective tissue of the inflamed intestinal wall.

[0008] The dosage form of mesalazine products on the market is mainly tablets, and its preparation process is mainly wet granulation. Unlike other conventional wet granulation products, the API mesalazine mostly exists in needle-shaped or rod-shaped polymorphic forms, showing a fluffy stacking state and poor fluidity. In the wet granulation process, this physical property is more likely to cause over-granulation or under-granulation, the granulation endpoint is more difficult to control, and the obtained soft materials are more diverse.

[0009] CN116098871A discloses a process for preparing mesalazine sustained-release granules, which comprises extruding a drug-containing soft material of a specific composition through a flat screen plate of a specific extrusion device, and obtaining a drug-containing strip that is compact and longer, and has no surface cracks. The prepared mesalazine sustained-release granules have a better effect of delaying and prolonging drug release.

[0010] CN118319873A discloses an enteric coating method for mesalazine enteric-coated tablets. By adjusting the coating formula and preparation process of the mesalazine enteric-coated tablets, the release amount of mesalazine in acid is reduced and the release amount of mesalazine in a high pH buffer is increased; at the same time, the difference in product quality between different batches and the same batch is reduced, and the stability of the mesalazine enteric-coated tablets is improved.

[0011] It can be seen that the research on the endpoint of mesalazine wet granulation in the prior art is relatively limited, and a new granulation method is urgently needed to solve the problem that the endpoint of mesalazine wet granulation is difficult to control, so as to prepare mesalazine tablets that meet the quality requirements. Summary of the invention

[0012] The object of the present invention is to provide a method for preparing a mesalazine soft material, a method for preparing a mesalazine tablet, and the mesalazine soft material and mesalazine tablet obtained by the above-mentioned preparation method, which overcome the above-mentioned defects of the prior art.

[0013] In a first aspect, the present invention provides a method for preparing a mesalazine soft material, comprising the following steps:

[0014] Providing an active ingredient with a bulk density of 0.27-0.35 g / mL;

[0015] dry-mixing the active ingredient with povidone, sodium carboxymethyl starch and hypromellose to obtain a basic granulation dry material;

[0016] Adding water to the basic granulation dry material for stirring and shearing to obtain a wet granulation soft material;

[0017] in,

[0018] The active ingredient is mesalazine or a pharmaceutically acceptable salt thereof; the weight of the water is 38-42% of the weight of the basic granulation dry material; the stirring and shearing are performed by a stirring paddle and a cutter of a granulator; wherein the rotation speed of the stirring paddle is 80-120 rpm; the rotation speed of the cutter is 900-1500 rpm; and the stirring and shearing time is 5-7 min.

[0019] The basic granulation dry material of the present invention can be stirred and sheared by a granulator, and preferably the granulator is GHL-100.

[0020] In a second aspect, the present invention provides a mesalazine soft material, which is prepared by the preparation method of the first aspect.

[0021] In a third aspect, the present invention provides a method for preparing mesalazine tablets, comprising the following steps:

[0022] Drying and dry granulating the soft material obtained by the preparation method of the first aspect to obtain dry granules;

[0023] mixing and lubricating the dry granules with microcrystalline cellulose, silicon dioxide, and magnesium stearate to obtain a total blend;

[0024] The total blend is tableted.

[0025] In a fourth aspect, the present invention provides a mesalazine tablet, which is prepared by the preparation method of the third aspect.

[0026] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention, as well as the technical features specifically described below (such as embodiments), can be combined with each other to form new or preferred technical solutions. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is the soft material 1-1 obtained in Comparative Example 1.

[0028] Figure 2 This is the soft material 2-1 obtained in Comparative Example 2.

[0029] Figure 3 This is the soft material 3-1 obtained in Invention Example 1.

[0030] Figure 4 This is the soft material 4-1 obtained in Invention Example 2.

[0031] Figure 5 This is the soft material 5-1 obtained in Invention Example 3. DETAILED DESCRIPTION

[0032] The present invention will be further described in detail below. Such description is for illustrative purposes only and is not intended to limit the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments. Those skilled in the art can make various modifications and changes without departing from the spirit of the present invention.

[0033] General Definitions and Terminology

[0034] Unless otherwise indicated, all publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0035] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the event of a conflict, the definitions provided herein shall prevail.

[0036] Unless otherwise indicated, all percentages, parts, ratios, etc. are by weight.

[0037] When providing quantity, concentration or other value or parameter as range, preferred range or preferred upper limit and lower limit or specific value, it should be understood as specifically disclosing all ranges formed by paired values ​​from any upper limit range or preferred value and any lower limit range or preferred value, regardless of whether the range is disclosed individually. Unless otherwise stated, when numerical range is quoted herein, described range refers to including its endpoints and integers and fractions within all such ranges. The scope of the present invention is not limited to the specific numerical value quoted when defining the range. For example, "0.015:1 to 0.030:1" encompasses 0.015:1, 0.016:1, 0.017:1, 0.018:1, 0.019:1, 0.020:1, 0.021:1, 0.022:1, 0.023:1, 0.024:1, 0.025:1, 0.026:1, 0.027:1, 0.028:1, 0.029:1, or 0.030:1, and any sub-range consisting of any two values ​​therein, e.g., 0.016:1 to 0.030:1, 0.018:1 to 0.028:1, 0.020:1 to 0.026:1, 0.021:1 to 0.024:1, 0.022:1 to 0.023:1, etc.

[0038] The terms "about" and "approximately" when used in conjunction with a numerical variable generally refer to the value of that variable and all values ​​of that variable are within the experimental error (e.g., within a 95% confidence interval for the mean) or within ±10% of the specified value, or within a wider range (e.g., within ±15%, within ±20%, within ±25%, or within ±30%).

[0039] The terms "comprises", "includes", "has", "contains" or "involves" and other variations thereof herein are inclusive or open-ended and do not exclude other unlisted elements or method steps. It will be understood by those skilled in the art that the above terms such as "comprising" encompass the meaning of "consisting of". The expression "consisting of" excludes any element, step or ingredient not specified. The expression "consisting essentially of" means that the scope is limited to the specified elements, steps or ingredients, plus the optional presence of elements, steps or ingredients that do not substantially affect the basic and novel features of the claimed subject matter. It will be understood that the expression "comprising" encompasses the expressions "consisting essentially of" and "consisting of".

[0040] The term "selected from..." means that one or more elements in the group listed later are independently selected and may include combinations of two or more elements.

[0041] Unless otherwise specified, the terms "combination thereof" and "mixture thereof" refer to a multi-component mixture of the elements, such as a two-component mixture, a three-component mixture, a four-component mixture and the maximum possible multi-component mixture.

[0042] The terms "one or more" or "at least one" as used herein refer to one, two, three, four, five, six, seven, eight, nine or more.

[0043] In addition, if the number of parts or components of the present invention is not indicated before, it means that there is no limit to the number of occurrences (or existence) of the parts or components. Therefore, it should be interpreted as including one or at least one, and the singular form of the parts or components also includes the plural form, unless the numerical value obviously represents the singular.

[0044] The term "stoichiometric ratio" refers to the mixing of various substances at a certain weight ratio. For example, in the present invention, the active ingredient (mesalazine or a pharmaceutically acceptable salt thereof), the carrier material and the optional pharmaceutically acceptable pharmaceutical excipients are mixed at a certain weight ratio.

[0045] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both occurring and not occurring of said event or circumstance.

[0046] The term "pharmaceutically acceptable" refers to a substance that is, within the scope of normal medical judgment, suitable for contact with the tissues of patients without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit-risk ratio, and effective for its intended use.

[0047] The term "pharmaceutically acceptable excipient" refers to those carrier materials that have no obvious irritation to the organism and do not damage the biological activity and performance of the active compound. "Pharmaceutically acceptable excipients" include, but are not limited to, glidants, sweeteners, fillers, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents or emulsifiers. Non-limiting examples of the carrier material include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols, etc. For additional information about the carrier, reference may be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0048] The term "active ingredient" refers to a chemical entity that is effective in treating or preventing a target disease or condition. In an embodiment of the present invention, the active ingredient is mesalazine or a pharmaceutically acceptable salt thereof.

[0049] The term "pharmaceutical preparation" and the like refer to a pharmaceutical composition administered to a patient in need of treatment, which can generally be in the following forms: powder, granules, pills, capsules, tablets, solutions, suspensions or patches, etc. In some embodiments, the mesalazine pharmaceutical preparation prepared by the method of the present invention is a tablet.

[0050] As used herein, the term "soft material" refers to a material obtained by wet granulation of an active ingredient optionally with a pharmaceutically acceptable excipient. For example, the soft material of the present invention is a material obtained by wet granulation of a basic granulation dry material obtained by dry mixing the active ingredient mesalazine with povidone, sodium carboxymethyl starch and hypromellose with water.

[0051] As used herein, the term "f2 similarity factor" or "f2 factor" refers to a reference value used to evaluate the similarity of two dissolution curves under the same dissolution conditions.

[0052] As used herein, the term "tapped density" refers to the mass per unit volume of powder in a container measured after being tapped under specified conditions.

[0053] As used herein, the term "bulk density" refers to the mass of powder per unit volume when a powder sample naturally fills a specified container.

[0054] Preparation method of mesalazine soft material

[0055] The present invention provides a method for preparing a mesalazine soft material, which comprises the following steps:

[0056] Providing an active ingredient with a bulk density of 0.27-0.35 g / mL;

[0057] dry-mixing the active ingredient with povidone, sodium carboxymethyl starch and hypromellose to obtain a basic granulation dry material;

[0058] Adding water to the basic granulation dry material for stirring and shearing to obtain a wet granulation soft material;

[0059] in,

[0060] The active ingredient is mesalazine or a pharmaceutically acceptable salt thereof; the weight of the water is 38-42% of the weight of the basic granulation dry material; the stirring and shearing are performed by a stirring paddle and a cutter of a granulator; wherein the rotation speed of the stirring paddle is 80-120 rpm; the rotation speed of the cutter is 900-1500 rpm; and the stirring and shearing time is 5-7 min.

[0061] In a preferred embodiment, the granulator is GHL-100.

[0062] Bulk density control

[0063] The present invention provides an active ingredient with a bulk density of 0.27-0.35 g / mL, including any method for adjusting the bulk density of the active ingredient or directly obtaining the active ingredient with the corresponding bulk density through commercial purchase. The method for adjusting the bulk density includes but is not limited to controlling the particle size of the active ingredient, optimizing the particle size distribution, etc. This bulk density range is conducive to the control of the endpoint of mesalazine wet granulation.

[0064] In some embodiments, the bulk density of the active ingredient of the present invention is controlled by commercially purchasing the active ingredient of the corresponding bulk density. For example, mesalamine having the bulk density of the present invention can be purchased from Cambrex Karlskoga AB, Sweden. The bulk density of the active ingredient of the present invention includes but is not limited to 0.27g / mL, 0.28g / mL, 0.29g / mL, 0.30g / mL, 0.31g / mL, 0.32g / mL, 0.33g / mL, 0.34g / mL or 0.35g / mL.

[0065] Preparation of dry materials for basic granulation

[0066] In the preparation method of the present invention, the active ingredient is dry-mixed with povidone, sodium carboxymethyl starch and hypromellose to prepare a basic granulation dry material. Therefore, the basic granulation dry material includes the active ingredient, povidone, sodium carboxymethyl starch and hypromellose.

[0067] In some embodiments, the active ingredient is dry mixed with povidone, sodium carboxymethyl starch and hypromellose by a granulator. For example, the basic granulation dry material is prepared by dry mixing with a granulator GHL-100.

[0068] The povidone, sodium carboxymethyl starch and hypromellose used in the present invention are all commercially available. Sodium carboxymethyl starch and hypromellose can be purchased from JRS Co., Ltd. The model of the povidone used in the present invention can be PVP K90, which can be purchased from Ashland Corporation.

[0069] The active ingredient of the present invention is mesalamine or a pharmaceutically acceptable salt thereof, preferably mesalamine. Mesalamine, also known as 5-aminosalicylic acid (structural formula shown below), is an organic compound with a chemical formula of C7H7NO3. It is an active ingredient of sulfasalazine (SASP) for treating ulcerative colitis and has a significant inhibitory effect on inflammation of the intestinal wall. Mesalamine can inhibit the synthesis of prostaglandins that cause inflammation and the formation of inflammatory mediators leukotrienes, thereby significantly inhibiting inflammation of the intestinal mucosa. Mesalamine can inhibit the synthesis of prostaglandins in a dose-dependent manner and reduce the release of prostaglandin E2 (PGE2) in human colonic mucosa.

[0070]

[0071] In some embodiments, the weight ratio of povidone to active ingredient is 0.070:1 to 0.080:1, for example 0.071:1, 0.072:1, 0.073:1, 0.074:1, 0.075:1, 0.076:1, 0.077:1, 0.078:1 or 0.079:1; preferably 0.073:1 to 0.077:1; more preferably 0.075:1.

[0072] In other embodiments, the weight ratio of sodium carboxymethyl starch to active ingredient is 0.020:1 to 0.030:1, for example 0.021:1, 0.022:1, 0.023:1, 0.024:1, 0.025:1, 0.026:1, 0.027:1, 0.028:1 or 0.029:1; preferably 0.023:1 to 0.027:1; more preferably 0.025:1.

[0073] In another embodiment, the weight ratio of hypromellose to active ingredient is 0.015:1 to 0.030:1, for example, 0.016:1, 0.017:1, 0.018:1, 0.019:1, 0.020:1, 0.021:1, 0.022:1, 0.023:1, 0.024:1, 0.025:1, 0.026:1, 0.027:1, 0.028:1 or 0.029:1; preferably 0.020:1 to 0.024:1; more preferably 0.022:1.

[0074] Preparation of soft materials

[0075] The preparation method of the invention obtains wet granulation soft material by adding water into basic granulation dry material for stirring and shearing.

[0076] The preparation method of the present invention uses purified water as a granulation solution. In the present invention, the water used for wet granulation can be added by any suitable means. For example, the water of the present invention is added to the basic granulation dry material by a pressure tank. The method of the present invention also controls the continuous addition time of water, for example, the duration of water addition is controlled to be about 1-10 minutes, such as about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes or about 9 minutes by the air pressure of the pressure tank; preferably 5-7 minutes; more preferably 6 minutes.

[0077] In addition, in the preparation method of the present invention, the weight of the water used for wet granulation is 38-42% of the weight of the basic granulation dry material, for example, 38.5%, 39%, 39.5%, 40%, 40.5%, 41% or 41.5%; preferably 38%, 40% and 42%. The amount of water in the granulation solution is conducive to the control of the endpoint of the mesalazine wet granulation.

[0078] In some embodiments, the preparation method of the present invention is prepared using a granulator, for example, a granulator GHL-100. In the granulator, the basic granulation dry materials are stirred and sheared by the rotation of the stirring blade and the cutting knife.

[0079] The present invention is conducive to the control of the endpoint of mesalazine wet granulation by the specific rotation speed of the stirring paddle and the cutting knife and the specific time of stirring and shearing during stirring and shearing. In the present invention, the rotation speed of the stirring paddle is 80-120rpm, for example, 80rpm, 85rpm, 90rpm, 95rpm, 100rpm, 105rpm, 110rpm, 115rpm or 120rpm; preferably 90-110rpm; more preferably 90rpm, 100rpm or 110rpm. In the present invention, the rotation speed of the cutting knife is 900-1500rpm, for example, 900rpm, 1000rpm, 1100rpm, 1200rpm, 1300rpm, 1400rpm or 1500rpm; preferably 1000-1400rpm; more preferably 1000rpm, 1200rpm or 1400rpm. In the present invention, the stirring and shearing time is 5-7 min, for example, 5 min, 5.5 min, 6.0 min, 6.5 min or 7 min; preferably 5 min, 6 min or 7 min.

[0080] The preparation method of the mesalazine soft material of the present invention can clearly and easily reach the end point of wet granulation by dry-mixing the active ingredient of a specific bulk density with povidone, sodium carboxymethyl starch and hydroxypropyl methylcellulose, adding an appropriate amount of water, and coordinating with a specifically selected stirring shearing speed and time, without over-granulation or under-granulation, greatly improving the controllability and stability of wet granulation, and obtaining a soft material with excellent properties (forming a mass when held and dispersing when touched), thereby laying a good foundation for the subsequent production process and detection and release of the product.

[0081] Therefore, the present invention also provides a soft material, which is prepared by the soft material preparation method of the present invention.

[0082] Preparation of Mesalazine Tablets

[0083] The present invention also uses the soft material prepared by the preparation method of the mesalazine soft material of the present invention, and further undergoes drying, dry granulation, mixed lubrication and tableting to prepare mesalazine tablets.

[0084] Preparation of dry granules

[0085] The soft material prepared by the method for preparing a soft material of the present invention is dried and dry granulated to obtain dry granules.

[0086] The method for preparing the soft material of the present invention is as described above.

[0087] For the drying step in the present invention, those skilled in the art can select a drying method commonly used in the art as needed, such as normal pressure drying, reduced pressure drying, boiling drying, etc. In the present invention, when the drying weight loss of the soft material particles is less than 1.0%, the dried soft material particles can be used for dry granulation.

[0088] In some embodiments, the present invention is dried by a fluidized bed, for example, by a fluidized bed Huttlin HGDC100. The drying time of the present invention is preferably about 60-180 min, such as 70 min, 80 min, 90 min, 100 min, 110 min, 120 min, 130 min, 140 min, 150 min, 160 min or 170 min. The fluidized bed inlet air temperature is preferably set to about 50-70 ° C. The fluidized bed inlet air volume is preferably about 700-1700 m 3 / h.

[0089] The dry granulation of the present invention is carried out by a dry granulator, for example, by a dry granulator Quadro Comil U10. In some embodiments, the rotation speed of the shearing knife in the dry granulator is 1200-1800rpm, for example, 1200rpm, 1300rpm, 1400rpm, 1500rpm, 1600rpm, 1700rpm or 1800rpm. In other embodiments, the size of the sieve used for dry granulation is 0.8-1.2mm, for example, 0.8mm, 0.9mm, 1.0mm, 1.016mm, 1.1mm or 1.2mm.

[0090] By means of the preparation method of the mesalazine soft material of the present invention, dry particles having the following properties can be obtained: the particle size distribution is relatively uniform, there is no excessive fine powder or excessively large particle size, the particles have good fluidity and compressibility, and there is no sticking in the tableting step, and there is no stratification with other materials in the mixing and lubrication process.

[0091] Preparation of the blend

[0092] The total blend of the present invention refers to the material obtained by mixing and lubricating the dry granules of the present invention with microcrystalline cellulose, silicon dioxide and magnesium stearate.

[0093] The dry granules of the present invention are mixed and lubricated with microcrystalline cellulose, silicon dioxide and magnesium stearate to obtain a total blend.

[0094] In some embodiments, the dry granules, microcrystalline cellulose, and silicon dioxide are mixed, and then magnesium stearate is added for lubrication to obtain a total blend.

[0095] In some embodiments, the weight of microcrystalline cellulose is 2.0%-3.0% of the weight of the prepared mesalazine tablet, for example, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8% or 2.9%; preferably 2.2%-2.6%; more preferably 2.4%.

[0096] In other embodiments, the weight of silicon dioxide is 0.1%-1.0% of the weight of the prepared mesalazine tablet, such as 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8% or 0.9%, preferably 0.4%-0.6%; more preferably 0.5%.

[0097] In another embodiment, the weight of magnesium stearate is 1.0%-2.0% of the weight of the prepared mesalazine tablet, for example 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8% or 1.9%; preferably 1.2%-1.6%; more preferably 1.4%.

[0098] The total mixture prepared by the method of the invention has suitable bulk density, tap density and Carr index.

[0099] In some embodiments, the bulk density of the total blend of the present invention is 0.52 g / mL-0.56 g / mL, for example, 0.53 g / mL, 0.54 g / mL or 0.55 g / mL; preferably 0.53 g / mL or 0.55 g / mL.

[0100] In some embodiments, the tap density of the total mixture of the present invention is 0.73 g / mL-0.75 g / mL, for example, 0.73 g / mL, 0.74 g / mL or 0.75 g / mL; preferably 0.73 g / mL or 0.75 g / mL.

[0101] Carr's index is used to describe the fluidity and stacking properties of particles, and is calculated as follows: Carr's index = (tap density - bulk density) / tap density × 100%. The total mixture prepared by the preparation method of the present invention has a suitable Carr's index relative to the active ingredient. In some embodiments, the Carr's index of the total mixture of the present invention is 22%-30%, for example, 22%, 23%, 24%, 24.66%, 25%, 26%, 27%, 27.40%, 28%, 29%, 29.33% or 30%; preferably 24.66%, 27.40% or 29.33%.

[0102] Tablet preparation

[0103] The present invention compresses the total mixture into tablets by a tablet press to obtain the tablets of the present invention. For example, the total mixture is compressed into tablets by a tablet press Fite P2020 to obtain tablets.

[0104] In some embodiments, the weight of mesalazine is 80.0%-90.0% of the weight of the prepared mesalazine tablet, for example 81.0%, 82.0%, 83.0%, 84.0%, 85.0%, 86.0%, 87.0%, 88.0% or 89.0%; preferably 84.0%-87.0%; more preferably 85.3%.

[0105] In some embodiments, the weight of povidone is 6.0%-7.0% of the weight of the prepared mesalazine tablet, for example 6.1%, 6.2%, 6.3%, 6.4%, 6.5%, 6.6%, 6.7%, 6.8% or 6.9%; preferably 6.2%-6.6%; more preferably 6.4%.

[0106] In some embodiments, the weight of sodium starch glycolate is 1.5%-2.5% of the weight of the prepared mesalazine tablet, for example 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3% or 2.4%; preferably 1.9%-2.3%; more preferably 2.1%.

[0107] In some embodiments, the weight of hypromellose is 1.5%-2.5% of the weight of the prepared mesalazine tablet, for example 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3% or 2.4%; preferably 1.7%-2.1%; more preferably 1.9%.

[0108] In some embodiments, the weight of microcrystalline cellulose is 2.0%-3.0% of the weight of the prepared mesalazine tablet, for example, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8% or 2.9%; preferably 2.2%-2.6%; more preferably 2.4%.

[0109] In some embodiments, the weight of silicon dioxide is 0.1%-1.0% of the weight of the prepared mesalazine tablet, such as 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8% or 0.9%, preferably 0.4%-0.6%; more preferably 0.5%.

[0110] In one embodiment, the weight of magnesium stearate is 1.0%-2.0% of the weight of the prepared mesalazine tablet, for example 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8% or 1.9%; preferably 1.2%-1.6%; more preferably 1.4%.

[0111] The soft material prepared by the soft material method of the present invention is further dried and dry granulated, then mixed and lubricated with microcrystalline cellulose, silicon dioxide and magnesium stearate, and the obtained total mixture is tableted to obtain mesalazine tablets, which have stable and controllable dissolution and release properties and can well achieve the expected sustained release effect.

[0112] Therefore, the present invention also provides a mesalazine tablet, which is prepared by the above-mentioned preparation method of the present invention. The present invention also relates to the use of the mesalazine tablet of the present invention in preparing a medicament for treating ulcerative colitis and Crohn's disease.

[0113] Beneficial Effects

[0114] In the process of commercial production of drugs, the fluctuation of material properties such as particle size, particle shape and moisture content of raw materials and auxiliary materials between different batches, as well as slight changes in equipment performance / process operation, make it very difficult for production personnel to judge the endpoint of wet granulation, which can easily lead to over-granulation or under-granulation, making it difficult to proceed to the next step of granulation and tableting, resulting in many batches of production failures. For sustained-release preparations, the results of wet granulation directly affect the speed of dissolution and release. If it is not well controlled, the dissolution of the product will not meet the product quality requirements and cannot be commercialized, which will bring great waste of production and testing resources to pharmaceutical companies.

[0115] The preparation method of the mesalazine soft material of the present invention solves many problems caused by the difficulty in controlling the endpoint of the wet granulation of mesalazine in actual production, such as poor repeatability caused by the uncontrollable granulation endpoint and unstable granulation effect.

[0116] The preparation method of the mesalazine soft material of the present invention can clearly and easily reach the end point of wet granulation by dry-mixing the active ingredient of a specific bulk density with povidone, sodium carboxymethyl starch and hydroxypropyl methylcellulose, adding an appropriate amount of water, and coordinating with a specifically selected stirring shearing speed and time, without over-granulation or under-granulation, greatly improving the controllability and stability of wet granulation, and obtaining a soft material with excellent properties (forming a mass when held and dispersing when touched), thereby laying a good foundation for the subsequent production process and detection and release of the product.

[0117] Furthermore, the dissolution and release of the mesalazine tablets prepared by the preparation method of the present invention becomes more stable and controllable, and the release in the body is stable and the absorption effect is excellent.

[0118] Example

[0119] Unless otherwise specified, reagents and starting materials used herein are commercially available.

[0120] In the following examples, mesalazine API (active ingredient) was purchased from Cambrex Karlskoga AB, Sweden; sodium carboxymethyl starch and hydroxypropyl methylcellulose were purchased from JRS Co., Ltd.; the model of povidone was PVP K90, purchased from Ashland; microcrystalline cellulose was purchased from FMC; silicon dioxide was purchased from Guangzhou Tianrun Pharmaceutical Co., Ltd.; and magnesium stearate was purchased from Shanghai Yunhong Chemical Preparation Excipient Technology Co., Ltd.

[0121] 1. Quality evaluation method

[0122] 1.1 Dissolution

[0123] Dissolution method USP II method (paddle method) Dissolution medium Phosphate buffer, pH 7.2: 900 mL Speed 100 rpm temperature 37.5°C Test dose 1.2 g (mesalazine) / cup

[0124] 1.2 Particle size distribution (PSD)

[0125]

[0126] 1.3 Bulk density / tapped density (BD / TD)

[0127]

[0128] Note: Bulk density and tap density are measured using the bulk density and tap density determination method 0993 in Part 4 of the Chinese Pharmacopoeia (2020 Edition); there is no tapping step when testing bulk density, and a tapping step is included when testing tap density.

[0129] 2. Composition of Mesalazine Tablets

[0130]

[0131] 3. Wet granulation process parameters of the inventive examples and comparative examples

[0132] Table 1 Wet granulation process parameters

[0133]

[0134] * The amount of granulation solution (i.e. purified water) is the weight percentage of the total weight of the basic granulation dry materials (active ingredient, sodium starch glycolate, PVP K90 and hypromellose).

[0135] Example 1: Comparative Example 1 - Preparation of Mesalazine Tablets Using Low Bulk Density Active Ingredients

[0136] Mesalazine tablets were prepared using mesalazine having a bulk density of about 0.24 g / mL as an active ingredient.

[0137] About 18 kg of active ingredient mesalazine, about 1.35 kg of PVP K90, 0.45 kg of sodium carboxymethyl starch and 0.40 kg of hypromellose were added into a granulator (GHL-100) for dry mixing to obtain basic granulation dry materials.

[0138] After dry mixing, 44% of the total weight of the basic granulation dry materials was sprayed into the granulator through a pressure tank, and the liquid addition time was controlled by the air pressure of the pressure tank for about 6 minutes. The stirring paddle and the cutter were turned on for wet granulation, wherein the speed of the cutter was 1600 rpm, the speed of the stirring paddle was 130 rpm, and the stirring and shearing time was 9 minutes to obtain soft material 1-1.

[0139] Transfer the soft material 1-1 to a fluidized bed (Huttlin HGDC100) for drying. The drying time is about 60-180 min, until the drying weight loss of the soft material particles is less than 1.0%. The inlet air temperature of the fluidized bed is set to about 60±10°C, and the inlet air volume is about 1200±500m 3 / h.

[0140] The dried soft material particles were passed through a dry granulator (Quadro Comil U10) for dry granulation. A fish scale screen with a size of 1.016 mm was used for dry granulation. The rotation speed of the shearing knife of the dry granulator was 1500±300 rpm, and dry particles 1-2 were obtained.

[0141] The dry particles 1-2, 0.5 kg of microcrystalline cellulose, and 0.1 kg of silicon dioxide were added into a hopper mixer for mixing, and then lubricated with 0.3 kg of magnesium stearate to obtain a mesalazine total blend 1-3.

[0142] The total blend was tableted using a tablet press (Fette P2020) to obtain mesalazine tablets 1-4.

[0143] Example 2: Comparative Example 2 - Preparation of Mesalazine Tablets Using High Bulk Density Active Ingredients

[0144] Mesalazine tablets were prepared using mesalazine having a bulk density of about 0.40 g / mL as an active ingredient.

[0145] About 18 kg of active ingredient mesalazine, about 1.35 kg of PVP K90, 0.45 kg of sodium carboxymethyl starch and 0.40 kg of hypromellose were added into a granulator (GHL-100) for dry mixing to obtain basic granulation dry materials.

[0146] After dry mixing, 36% of the total weight of the basic granulation dry materials was sprayed into the granulator through a pressure tank, and the liquid addition time was controlled by the air pressure of the pressure tank for about 6 minutes. The stirring paddle and the cutter were turned on for wet granulation, wherein the speed of the cutter was 800 rpm, the speed of the stirring paddle was 70 rpm, and the stirring and shearing time was 3 minutes to obtain soft material 2-1.

[0147] Transfer the soft material 2-1 to a fluidized bed (Huttlin HGDC100) for drying. The drying time is about 60-180 minutes, until the drying weight loss of the soft material particles is less than 1.0%. The fluidized bed inlet air temperature is set to about 60±10℃, and the inlet air volume is about 1200±500m 3 / h.

[0148] The dried soft material particles were passed through a dry granulator (Quadro Comil U10) for dry granulation. A fish scale screen with a size of 1.016 mm was used for dry granulation. The rotation speed of the shearing knife of the dry granulator was 1500±300 rpm, and dry granules 2-2 were obtained.

[0149] The dry granules 2-2, 0.5 kg of microcrystalline cellulose, and 0.1 kg of silicon dioxide were added into a hopper mixer for mixing, and then lubricated with 0.3 kg of magnesium stearate to obtain a mesalazine total blend 2-3.

[0150] The total blend was tableted using a tablet press (Fette P2020) to obtain mesalazine tablets 2-4.

[0151] Example 3 Invention Example 1 - Preparation of Mesalazine Tablets Using Bulk Density Active Ingredients of the Present Invention

[0152] Mesalazine tablets were prepared using mesalazine having a bulk density of about 0.27 g / mL as an active ingredient.

[0153] About 18 kg of active ingredient mesalazine, about 1.35 kg of PVP K90, 0.45 kg of sodium carboxymethyl starch and 0.40 kg of hypromellose were added into a granulator (GHL-100) for dry mixing to obtain basic granulation dry materials.

[0154] After dry mixing, 42% of the total weight of the basic granulation dry materials was sprayed into the granulator through a pressure tank, and the liquid addition time was controlled by the air pressure of the pressure tank for about 6 minutes. The stirring paddle and the cutter were turned on for wet granulation, wherein the speed of the cutter was 1400 rpm, the speed of the stirring paddle was 110 rpm, and the stirring and shearing time was 7 minutes to obtain soft material 3-1.

[0155] Transfer the soft material 3-1 to a fluidized bed (Huttlin HGDC100) for drying. The drying time is about 60-180 minutes, until the drying weight loss of the soft material particles is less than 1.0%. The fluidized bed air inlet temperature is set to about 60±10℃, and the air volume is about 1200±500m 3 / h.

[0156] The dried soft material particles were passed through a dry granulator (Quadro Comil U10) for dry granulation. A fish scale screen with a size of 1.016 mm was used for dry granulation. The rotation speed of the shearing knife of the dry granulator was 1500±300 rpm, and dry particles 3-2 were obtained.

[0157] The dry particles 3-2, 0.5 kg of microcrystalline cellulose, and 0.1 kg of silicon dioxide were added into a hopper mixer for mixing, and then lubricated with 0.3 kg of magnesium stearate to obtain a mesalazine total blend 3-3.

[0158] The total blend was tableted using a tablet press (Fette P2020) to obtain mesalazine tablets 3-4.

[0159] Example 4 Invention Example 2 - Preparation of Mesalazine Tablets Using Bulk Density Active Ingredients of the Present Invention

[0160] Mesalazine tablets were prepared using mesalazine having a bulk density of about 0.30 g / mL as an active ingredient.

[0161] About 18 kg of active ingredient mesalazine, about 1.35 kg of PVP K90, 0.45 kg of sodium carboxymethyl starch and 0.40 kg of hypromellose were added into a granulator (GHL-100) for dry mixing to obtain basic granulation dry materials.

[0162] After dry mixing, 40% of the total weight of the basic granulation dry materials was sprayed into the granulator through a pressure tank, and the liquid addition time was controlled by the air pressure of the pressure tank for about 6 minutes. The stirring paddle and the cutter were turned on for wet granulation, wherein the speed of the cutter was 1200 rpm, the speed of the stirring paddle was 100 rpm, and the stirring and shearing time was 6 minutes to obtain soft material 4-1.

[0163] Transfer the soft material 4-1 to a fluidized bed (Huttlin HGDC100) for drying. The drying time is about 60-180 minutes, until the drying weight loss of the soft material particles is less than 1.0%. The fluidized bed air inlet temperature is set to about 60±10℃, and the air volume is about 1200±500m 3 / h.

[0164] The dried soft material particles were passed through a dry granulator (Quadro Comil U10) for dry granulation. A fish scale screen with a size of 1.016 mm was used for dry granulation. The rotation speed of the shearing knife of the dry granulator was 1500±300 rpm, and dry particles 4-2 were obtained.

[0165] The dry granules 4-2, 0.5 kg of microcrystalline cellulose, and 0.1 kg of silicon dioxide were added into a hopper mixer for mixing, and then lubricated with 0.3 kg of magnesium stearate to obtain a mesalazine total blend 4-3.

[0166] The total blend was tableted using a tablet press (Fette P2020) to obtain mesalazine tablets 4-4.

[0167] Example 5 Invention Example 3 - Preparation of Mesalazine Tablets Using Bulk Density Active Ingredients of the Present Invention

[0168] Mesalazine tablets were prepared using mesalazine having a bulk density of about 0.35 g / mL as an active ingredient.

[0169] About 18 kg of active ingredient mesalazine, about 1.35 kg of PVP K90, 0.45 kg of sodium carboxymethyl starch and 0.40 kg of hypromellose were added into a granulator (GHL-100) for dry mixing to obtain basic granulation dry materials.

[0170] After dry mixing, 38% of the total weight of the basic granulation dry materials was sprayed into the granulator through a pressure tank, and the liquid addition time was controlled by the air pressure of the pressure tank for about 6 minutes. The stirring paddle and the cutter were turned on for wet granulation, wherein the speed of the cutter was 1000 rpm, the speed of the stirring paddle was 90 rpm, and the stirring and shearing time was 5 minutes to obtain soft material 5-1.

[0171] The soft material 5-1 is transferred to a fluidized bed (Huttlin HGDC100) for drying. The drying time is about 60-180 minutes, until the drying weight loss of the soft material particles is less than 1.0%. The inlet air temperature of the fluidized bed is set to about 60±10℃, and the inlet air volume is about 1200±500m 3 / h.

[0172] The dried soft material granules were passed through a dry granulator (Quadro Comil U10) for dry granulation. A fish scale screen with a size of 1.016 mm was used for dry granulation. The rotation speed of the shearing knife of the dry granulator was 1500±300 rpm, and dry granules 5-2 were obtained.

[0173] The dry granules 5-2, 0.5 kg of microcrystalline cellulose, and 0.1 kg of silicon dioxide were added into a hopper mixer for mixing, and then lubricated with 0.3 kg of magnesium stearate to obtain a mesalazine total blend 5-3.

[0174] The total blend was tableted using a tablet press (Fette P2020) to obtain mesalazine tablets 5-4.

[0175] 4. Characteristic evaluation

[0176] (1) Soft material properties

[0177] Soft material 1-1, insufficient granulation, weak viscosity, powdery, such as Figure 1 As shown; and it does not form a ball when held.

[0178] Soft material 2-1, over-granulation, too sticky, in large clumps, such as Figure 2 As shown; and it cannot be scattered when touched.

[0179] Soft material 3-1, fully granulated, suitable viscosity, in small granules, such as Figure 3 As shown; it can be held in a ball, but will fall apart when touched.

[0180] Soft material 4-1, fully granulated, suitable viscosity, in small granules, such as Figure 4 As shown; it can be held in a ball, but will fall apart when touched.

[0181] Soft material 5-1, fully granulated, suitable viscosity, in small granules, such as Figure 5 As shown; it can be held in a ball, but will fall apart when touched.

[0182] (2) Particle size distribution of dry particles

[0183] Table 2 Particle size distribution of dry particles

[0184]

[0185] Note: The particle size is measured using the particle size and particle size distribution determination method in Part 4 0982 of the Chinese Pharmacopoeia (2020 Edition).

[0186] (3) Compressibility of the mixture

[0187] Table 3 Bulk density / tapped density of the total mixture

[0188] Total mixture 1-3 2-3 3-3 4-3 5-3 Bulk density BD 0.47g / mL 0.58g / mL 0.53g / mL 0.55g / mL 0.53g / mL Tap density TD 0.79g / mL 0.72g / mL 0.73g / mL 0.73g / mL 0.75g / mL <![CDATA[Carr Index * / %]]> 40.51 19.44 27.40 24.66 29.33

[0189] Note: * The calculation formula of Carr's index is: Carr's index = (tapped density - bulk density) / tapped density × 100%.

[0190] Tableting test: When tableting was performed using the total blends 3-3, 4-3 and 5-3, no sticking occurred and the tableting was performed normally. In contrast, when tableting was performed using the total blend 1-3, severe sticking occurred and the tableting could not be performed normally.

[0191] From Table 2, Table 3 and the above-mentioned tableting test results, it can be seen that:

[0192] When the bulk density of the active ingredient mesalazine is not greater than 0.24 g / mL, it is difficult to fully granulate, the proportion of dry granules with a particle size distribution less than 106 μm is 40%, there is a lot of fine powder, poor compressibility and fluidity, the tablets stick to the punches, and frequent cleaning is required. In addition, the tablet weight obtained by tableting fluctuates greatly (the deviation exceeds 5%), which does not meet the quality requirements;

[0193] When the bulk density of the active ingredient mesalazine is not less than 0.40 g / mL, the granulation is excessive and a longer drying time is required. The proportion of dry granules with a particle size distribution greater than 425 μm is 46%. The particle size is too large, which easily causes the granules and the added materials to be separated after drying. This in turn leads to uneven filling of the granules and the added excipients during tableting, which makes the compressibility of many tablets worse, and the friability exceeds 1%, which does not meet the quality requirements.

[0194] When the bulk density of the active ingredient is maintained at 0.27-0.35 g / mL, the granulation is sufficient, the particle size distribution of the dry particles is relatively uniform, showing a normal distribution trend, and the compressibility and fluidity are both good.

[0195] (4) Comparison of dissolution of mesalazine tablets

[0196] Table 4 Dissolution comparison of mesalazine tablets

[0197]

[0198] *1 The reference substance is produced by Takeda Pharmaceuticals USA, Inc. The product is a sample with the outer enteric coating removed, and the product batch number is 9937280; *2 The similarity factor (f2) is a parameter that measures the similarity of two dissolution curves, that is, the similarity between the example and the reference product.

[0199] According to the results in Table 4:

[0200] When the bulk density of the active ingredient mesalazine is 0.27-0.35 g / mL, the dissolution similarity factor (f2) of the tablets (tablets 3-4, tablets 4-4 and tablets 5-4) prepared by the method of the present invention and the reference substance is greater than 73, and the dissolution of the tablets meets the quality requirements.

[0201] When the bulk density of the active ingredient mesalazine was no more than 0.24 g / mL, the dissolution similarity factor (f2) of the prepared tablets (tablets 1-4) and that of the reference substance was 41 (<50). The dissolution and release of the tablets were relatively fast, failing to achieve the expected sustained-release effect, and were not similar to the dissolution and release of the reference substance.

[0202] When the bulk density of the active ingredient mesalazine was not less than 0.40 g / mL, the dissolution similarity factor (f2) of the prepared tablets (tablets 2-4) and that of the reference substance was 26 (<50), and the dissolution release of the tablets was seriously slow and not similar to that of the reference substance.

[0203] The results of the above embodiments show that the preparation method of the mesalazine soft material of the present invention can clearly and easily reach the end point of the mesalazine wet granulation, achieve the effect of sufficient granulation, and neither over-granulation nor under-granulation will occur, which greatly improves the controllability and stability of the wet granulation, and obtains a soft material with excellent properties (forming a mass when held and dispersing when touched).

[0204] By means of the preparation method of the present invention, mesalazine can reach a sufficient and appropriate wet granulation endpoint in wet granulation, and the state of the obtained soft material, the particle size distribution of dry particles, the tableting test results, and the dissolution and release results indicate that the preparation method of the present invention can obtain a soft material with excellent properties, dry particles with uniform particle size distribution, a total mixture that does not cause sticking and can be normally tableted, and mesalazine tablets with stable and controllable dissolution and release properties.

[0205] In addition, the dissolution and release of the mesalazine tablets prepared by the preparation method of the present invention become more stable and controllable, and the dissolution, content and other data in vitro are not significantly different from those of the reference preparation tablet cores, and the release in vivo is stable and the absorption effect is excellent.

[0206] The embodiments of the present invention are described in detail above, but the contents are only preferred embodiments of the present invention and cannot be considered to limit the scope of implementation of the present invention. The true scope and spirit of the present invention are shown by the attached claims, and the description and embodiments are only exemplary.

Claims

1. A method for preparing a mesalazine soft material, characterized in that: It includes the following steps: Providing an active ingredient with a bulk density of 0.27-0.35 g / mL; dry-mixing the active ingredient with povidone, sodium carboxymethyl starch and hypromellose to obtain a basic granulation dry material; Adding water to the basic granulation dry material for stirring and shearing to obtain a wet granulation soft material; in, The active ingredient is mesalazine or a pharmaceutically acceptable salt thereof; The weight of the water is 38-42% of the weight of the basic granulation dry material; The stirring and shearing is carried out by the stirring blade and the cutting knife of the granulator; in, The rotation speed of the stirring paddle is 80-120 rpm; The rotation speed of the cutter is 900-1500rpm; The stirring and shearing time is 5-7 minutes.

2. The preparation method according to claim 1, characterized in that The active ingredient is mesalazine; and / or The povidone is PVP K90.

3. The preparation method according to claim 1, characterized in that: The weight ratio of the povidone to the active ingredient is 0.070:1 to 0.080:1; preferably 0.075:1; and / or The weight ratio of the sodium carboxymethyl starch to the active ingredient is 0.020:1 to 0.030:1; preferably 0.025:1; and / or The weight ratio of the hypromellose to the active ingredient is 0.015:1 to 0.030:1, preferably 0.022:

1.

4. The preparation method according to claim 1, characterized in that: The granulator is GHL-100; and / or The duration of adding water is 1-10 min, preferably 5-7 min, more preferably 6 min; and / or The rotation speed of the stirring paddle is 90-110 rpm; and / or The rotation speed of the cutter is 1000-1400 rpm.

5. A mesalazine soft material, characterized in that: The invention is prepared by the preparation method described in any one of claims 1 to 4.

6. A method for preparing mesalazine tablets, characterized in that: It includes the following steps: Drying and dry granulating the soft material obtained by the preparation method according to any one of claims 1 to 4 to obtain dry granules; mixing and lubricating the dry granules with microcrystalline cellulose, silicon dioxide and magnesium stearate to obtain a total blend; The total blend is tableted.

7. The preparation method according to claim 6, characterized in that: The endpoint of the drying is that the drying weight loss of the soft material particles used for drying is less than 1.0%; Preferably, The drying is carried out by a fluidized bed, preferably a Huttlin HGDC100; More preferably, The drying time is 60-180 min; and / or The air inlet temperature of the drying fluidized bed is 50-70°C; and / or The air volume of the drying fluidized bed is 700-1700m 3 / h.

8. The preparation method according to claim 6, characterized in that: The dry granulation is performed by a dry granulator, preferably a Quadro Comil U10; Preferably, The rotation speed of the shearing knife in the dry granulator is 1200-1800 rpm; and / or The sieve size used for the dry granulation is 0.8-1.2 mm, preferably 1.016 mm.

9. The preparation method according to claim 6, characterized in that: The weight of the mesalazine is 80.0%-90.0%, preferably 85.3% of the weight of the mesalazine tablet; and / or The weight of the povidone is 6.0%-7.0%, preferably 6.4% of the weight of the mesalazine tablet; and / or The weight of the sodium carboxymethyl starch is 1.5%-2.5%, preferably 2.1% of the weight of the mesalazine tablet; and / or The weight of the hypromellose is 1.5%-2.5%, preferably 1.9% of the weight of the mesalazine tablet; and / or The weight of the microcrystalline cellulose is 2.0%-3.0%, preferably 2.4% of the weight of the mesalazine tablet; and / or The weight of the silicon dioxide is 0.1%-1.0%, preferably 0.5%, of the weight of the mesalazine tablet; and / or The weight of the magnesium stearate is 1.0%-2.0% of the weight of the mesalazine tablet, preferably 1.4%.

10. A mesalazine tablet, characterized in that: It is prepared by the preparation method described in any one of claims 6 to 9.

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