Indobufen pharmaceutical composition, tablet and preparation method

Abstract

The invention relates to the technical field of pharmaceutical preparations, and particularly discloses an indobufen pharmaceutical composition, a tablet and a preparation method. According to the embodiment of the invention, indobufen, ground lactose and an internally added lubricant are co-crushed, the D90 particle size of the co-crushed material is controlled to be 10-40 [mu] m, then spray-dried lactose, microcrystalline cellulose and an internally added disintegrating agent are added for dry granulation, and finally an externally added disintegrating agent and an externally added lubricant are added for tabletting to prepare the indobufen tablet. Through the process, the prepared material is good in compressibility, the problems of sticking, tablet cracking, low hardness and the like in the tabletting process of indobufen are solved, meanwhile, the dissolution level of the prepared indobufen tablet in an acid medium is remarkably improved, the clinical effect of the product can be better exerted, and therefore replacement of an original product can be achieved; and the preparation is simple in production process, easy to realize large-scale industrial production, and relatively high in popularization and application value.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to an indobufen pharmaceutical composition, tablet and a preparation method thereof. Background Art

[0002] Indobufen, chemically known as (±)2-[4-(1-oxo-2-isoindolinyl)phenyl]butyric acid, is a derivative of isoindolinylphenylbutyric acid and an inhibitor of platelet aggregation. It was first launched in Italy under the trade name Ibustrin, and is currently available in other European countries, South Korea, and China. Indobufen is mainly used to treat ischemic cardiovascular disease, ischemic cerebrovascular disease, and venous thrombosis caused by arteriosclerosis, and can also be used to prevent thrombosis during hemodialysis.

[0003] Indobufen is a white crystalline powder, slightly soluble in acetone, slightly soluble in methanol and ethanol, insoluble in water, and almost insoluble in acidic media with a pH of 1.0 to 5.0. Indobufen itself has strong hydrophobicity, is easy to aggregate, has poor dispersibility, and poor fluidity. The formulation composition of the reference preparation listed in Europe is: lactose, microcrystalline cellulose, sodium carboxymethyl starch, magnesium dodecyl sulfate, and magnesium stearate. Most of the products on the market are prepared by wet granulation. No adhesive is used in the product formulation composition. The granules are prepared by wet granulation and tableting based on the viscosity of the raw material itself and the effect of the excipients. However, the granules prepared in this way have poor compressibility, and are prone to problems such as sticking, cracking, and low hardness during tableting. When the reference preparation product was inspected for appearance, it was found that there was an obvious problem of one-sided defects on the surface of the product due to sticking. In addition, the dissolution amount of indobufen in an acidic medium with a pH of 1.0 to 5.0 is extremely low, less than 12%, which makes the product's bioavailability in the gastrointestinal tract low. Therefore, it is necessary to provide a preparation process of indobufen tablets which can effectively improve the quality of indobufen tablets and increase their availability in the gastrointestinal tract. Summary of the invention

[0004] In view of the problems of one-sided defects and low gastrointestinal bioavailability of existing indobufen tablets, the present invention provides an indobufen pharmaceutical composition, tablets and a preparation method.

[0005] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0006] An indobufen pharmaceutical composition comprising indobufen co-crushed material, spray-dried lactose, an external lubricant, a disintegrant and microcrystalline cellulose;

[0007] The indobufen co-crushed material comprises indobufen, ground lactose and an internally added lubricant.

[0008] Indobufen itself has strong hydrophobicity, is easy to aggregate into agglomerates, has poor dispersibility and poor fluidity. The indobufen pharmaceutical composition provided by the present invention uses the co-crushed product of indobufen, ground lactose and internally added lubricant as raw materials, increases the contact specific surface area of ​​indobufen and water-soluble auxiliary materials, can improve the solubility of indobufen in acidic medium, thereby being beneficial to improving the bioavailability of indobufen in the gastrointestinal tract, and at the same time, indobufen, ground lactose and internally added lubricant are made into the co-crushed product, which can significantly improve the dispersibility and fluidity of indobufen in auxiliary materials, improve its compressibility in preparations, and is of great significance for improving the formability of tablets and reducing defects (such as cracking, sticking, etc.) in the production process.

[0009] Furthermore, the external lubricant includes magnesium stearate.

[0010] Furthermore, the internal lubricant includes one or both of magnesium dodecyl sulfate and sodium dodecyl sulfate.

[0011] Furthermore, the disintegrant is carboxymethylcellulose calcium.

[0012] Furthermore, the particle size D90 of the indobufen is 10 μm to 60 μm.

[0013] Furthermore, the particle size D90 of the indobufen co-crushed product is 10 μm to 40 μm.

[0014] Controlling the particle size of the indobufen co-crushed product within the above range can effectively improve the dissolution rate of indobufen in an acidic medium and the solubility of the drug in an acidic medium, thereby helping to improve the bioavailability of indobufen in the gastrointestinal tract. At the same time, controlling the particle size of the co-crushed product within the above range is conducive to more uniform dispersion of indobufen in the excipients, which plays a very important role in ensuring the uniformity of the indobufen content and the release characteristics in the preparation.

[0015] Furthermore, the average particle size of the spray-dried lactose is 75 μm to 200 μm.

[0016] Furthermore, the average particle size of the ground lactose is 20 μm to 60 μm.

[0017] The particle size of the milled lactose matches that of the indobufen to improve the homogeneity and flowability of the mixture.

[0018] Furthermore, the mass ratio of the ground lactose to indobufen is 1:4 to 1:1; and the spray-dried lactose is 10% to 30% of the total mass of the indobufen pharmaceutical composition.

[0019] Furthermore, the mass ratio of the ground lactose to indobufen is 1:2; and the spray-dried lactose is 10% to 20% of the total mass of the indobufen pharmaceutical composition.

[0020] The preferred particle size of the ground lactose and the mass ratio of the ground lactose to indobufen are beneficial to improving the uniformity of the co-crushed material. At the same time, the particle size control and addition ratio of the ground lactose are also beneficial to improving the solubility and dissolution rate of indobufen, thereby helping to improve the bioavailability of indobufen.

[0021] Furthermore, the microcrystalline cellulose accounts for 5% to 20% of the total mass of the indobufen pharmaceutical composition.

[0022] Preferably, the microcrystalline cellulose accounts for 7% to 15% of the total mass of the indobufen pharmaceutical composition.

[0023] The fluidity of indobufen raw material is poor. Using spray-dried lactose and microcrystalline cellulose as fillers can improve the compressibility of the material, reduce the dosage deviation of indobufen raw material in the preparation, and promote dissolution and disintegration.

[0024] Furthermore, the internal lubricant is 0.1% to 2% of the total mass of the indobufen pharmaceutical composition, and the external lubricant is 0.25% to 1.5% of the total mass of the indobufen pharmaceutical composition.

[0025] Preferably, the internal lubricant accounts for 0.25% to 1.5% of the total mass of the indobufen pharmaceutical composition, and the external lubricant accounts for 0.5% to 1.25% of the total mass of the indobufen pharmaceutical composition.

[0026] The indobufen raw material has poor fluidity, and the raw and auxiliary materials are not easy to mix evenly. The present invention uses magnesium stearate as an external lubricant and magnesium dodecyl sulfate and / or sodium dodecyl sulfate as an internal lubricant to improve the compressibility in tablet production. In addition, the hardness and smoothness of the prepared tablets can also be improved.

[0027] Furthermore, the disintegrant is 5% to 15% of the total mass of the indobufen pharmaceutical composition.

[0028] Preferably, the disintegrant is 7% to 12% of the total mass of the indobufen pharmaceutical composition.

[0029] The preferred disintegrant and the amount of disintegrant added can increase the disintegration rate of the indobufen tablet and improve the dissolution rate.

[0030] The present invention also provides an indobufen tablet, which is prepared from any one of the above-mentioned indobufen pharmaceutical compositions.

[0031] As a specific embodiment of the present invention, the indobufen tablet contains 200 mg of indobufen (single dose).

[0032] As a specific embodiment of the present invention, each indobufen tablet comprises: 200 mg of indobufen, 50 mg to 200 mg of ground lactose, 36.4 mg to 78 mg of microcrystalline cellulose, 36.4 mg to 62.4 mg of disintegrant, 0.52 mg to 10.4 mg of internal lubricant, 52 mg to 104 mg of spray-dried lactose, and 2.6 mg to 6.5 mg of external lubricant.

[0033] The present invention also provides a method for preparing the indobufen tablet, comprising the following steps:

[0034] S1, mixing indobufen, ground lactose and an internal lubricant uniformly, and crushing to obtain indobufen co-crushed material;

[0035] S2, mixing the indobufen co-crushed material, microcrystalline cellulose, part of the disintegrant and spray-dried lactose uniformly, and dry granulating to obtain granules;

[0036] S3, mixing the granules with the remaining disintegrant and the external lubricant evenly, and tableting to obtain indobufen tablets.

[0037] The preparation method of indobufen tablets provided by the present invention comprises the following steps: indobufen, ground lactose and an internal lubricant are pulverized together, and then microcrystalline cellulose, a disintegrant and spray-dried lactose are added to perform dry granulation, so that the obtained granules have good fluidity and high compressibility, and the problems of flakes, sticking and low hardness occurring in the tableting process caused by poor fluidity, poor dispersibility and poor formability of the raw materials in the traditional wet granulation are solved; at the same time, indobufen, ground lactose and an internal lubricant are pulverized together to increase the contact specific surface area between the active component and the water-soluble auxiliary material, and the disintegrant and the lubricant are added internally and externally respectively to balance the disintegration and dissolution characteristics of the tablets, so that the dissolution amount of the indobufen tablets in the acidic medium is significantly improved compared with the reference preparation, the bioavailability of the indobufen tablets in the gastrointestinal tract is improved, and a good replacement for the original product can be achieved.

[0038] Further, in S2, indobufen, ground lactose and internal lubricant are co-crushed by a hammer mill. Exemplarily, the operating frequency of the hammer mill is 30 Hz.

[0039] Furthermore, in S2, after the dry granulation, the process further comprises: passing the granulated material through a 20-mesh sieve for dry granulation.

[0040] Furthermore, the mass ratio of the disintegrant added in S2 to the disintegrant added in S3 is 1:1.

[0041] It should be noted that the tablet weight difference of indobufen tablets is required to be ±5%, the hardness range is 100N to 220N, and the disintegration time limit is 3min to 8min.

[0042] The present invention prepares indobufen tablets by dry granulation, and the prepared indobufen tablets have faster disintegration speed and dissolution rate. Compared with the reference preparation, the solubility in the acidic medium is significantly improved, which is helpful to increase the absorption and utilization of the product. At the same time, the quality of the indobufen tablets is significantly improved, without obvious cracks and unilateral defects, etc., and can achieve a good replacement for the original product. The preparation process is simple, the repeatability is good, and it is easy to realize large-scale industrial production. DETAILED DESCRIPTION

[0043] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0044] In order to better illustrate the present invention, further examples are given below.

[0045] The particle size D90 of the indobufen raw material used in the following examples and comparative examples is 16.2 μm; the average particle size of the spray-dried lactose is 100 μm; and the average particle size of the ground lactose is 30 μm.

[0046] Example 1

[0047] This embodiment provides an indobufen tablet, and the prescription dosage (single tablet dosage) is shown in the following table:

[0048]

[0049]

[0050] The preparation method of the above-mentioned indobufen tablets is as follows:

[0051] Step 1, adding indobufen, ground lactose and magnesium dodecyl sulfate into a mixer hopper, mixing at a speed of 10 rpm for 20 min, then adding into a hammer mill, setting the frequency to 30 Hz, and co-crushing to D90 = 13.6 μm to obtain a co-crushed product;

[0052] Step 2: Add the co-crushed product, microcrystalline cellulose, calcium carboxymethyl cellulose and spray-dried lactose into the mixer hopper, mix at 10 rpm for 20 min, and then add them into the dry granulator for dry granulation. Set the vertical feed speed to 50 Hz, the horizontal feed speed to 120 Hz, the roller speed to 8 rpm, and the oil pump pressure to 6.5 KN. After the granulation, use a 20-mesh screen to dry granulate to obtain granules.

[0053] Step 3: Add additional carboxymethylcellulose calcium to the above granules, mix in a mixer at 10 rpm for 20 min, then add magnesium stearate and continue mixing for 8 min, and use a high-speed tablet press to tablet to obtain indobufen tablets, which are required to have a tablet weight difference of ±5%, a tablet core disintegration time of 3 to 8 min, and a hardness of 100 to 220 N.

[0054] Example 2

[0055] This embodiment provides an indobufen tablet, and the prescription dosage (single tablet dosage) is shown in the following table:

[0056] Components Mass / mg Indobufen 200 Grind lactose 145 Microcrystalline Cellulose 57.6 Add carboxymethylcellulose calcium 26 Magnesium Lauryl Sulfate 5.2 Add calcium carboxymethyl cellulose 26 Spray dried lactose 55 Magnesium Stearate 5.2

[0057] The preparation method of the above-mentioned indobufen tablets is as follows:

[0058] Step 1, adding indobufen, ground lactose and magnesium dodecyl sulfate into a mixer hopper, mixing at a speed of 10 rpm for 20 min, then adding into a hammer mill, setting the frequency to 30 Hz, and co-crushing to D90 = 25.7 μm to obtain a co-crushed product;

[0059] Step 2: Add the co-crushed product, microcrystalline cellulose, calcium carboxymethyl cellulose and spray-dried lactose into the mixer hopper, mix at 10 rpm for 20 min, and then add them into the dry granulator for dry granulation. Set the vertical feed speed to 50 Hz, the horizontal feed speed to 120 Hz, the roller speed to 8 rpm, and the oil pump pressure to 6.5 KN. After the granulation, use a 20-mesh screen to dry granulate to obtain granules.

[0060] Step 3: Add additional carboxymethylcellulose calcium to the above granules, mix in a mixer at 10 rpm for 20 min, then add magnesium stearate and continue mixing for 8 min, and use a high-speed tablet press to tablet to obtain indobufen tablets, which are required to have a tablet weight difference of ±5%, a tablet core disintegration time of 3 to 8 min, and a hardness of 100 to 220 N.

[0061] Example 3

[0062] This embodiment provides an indobufen tablet, and the prescription dosage (single tablet dosage) is shown in the following table:

[0063] Components Mass / mg Indobufen 200 Grind lactose 100 Microcrystalline Cellulose 57.6 Add carboxymethylcellulose calcium 26 Sodium Lauryl Sulfate 5.2 Add calcium carboxymethyl cellulose 26 Spray dried lactose 100 Magnesium Stearate 5.2

[0064] The preparation method of the above-mentioned indobufen tablets is as follows:

[0065] Step 1, adding indobufen, ground lactose and sodium lauryl sulfate into a mixer hopper, mixing at a speed of 10 rpm for 20 min, then adding into a hammer mill, setting the frequency to 30 Hz, and co-crushing to D90 = 37.7 μm to obtain a co-crushed product;

[0066] Step 2: Add the co-crushed product, microcrystalline cellulose, calcium carboxymethyl cellulose and spray-dried lactose into the mixer hopper, mix at 10 rpm for 20 min, and then add them into the dry granulator for dry granulation. Set the vertical feed speed to 50 Hz, the horizontal feed speed to 120 Hz, the roller speed to 8 rpm, and the oil pump pressure to 6.5 KN. After the granulation, use a 20-mesh screen to dry granulate to obtain granules.

[0067] Step 3: Add additional carboxymethylcellulose calcium to the above granules, mix in a mixer at 10 rpm for 20 min, then add magnesium stearate and continue mixing for 8 min, and use a high-speed tablet press to tablet to obtain indobufen tablets, which are required to have a tablet weight difference of ±5%, a tablet core disintegration time of 3 to 8 min, and a hardness of 100 to 220 N.

[0068] Example 4

[0069] This embodiment provides an indobufen tablet, and the prescription dosage (single tablet dosage) is shown in the following table:

[0070] Components Mass / mg Indobufen 200 Grind lactose 100 Microcrystalline Cellulose 42 Add carboxymethylcellulose calcium 36.4 Magnesium Lauryl Sulfate 5.2 Add calcium carboxymethyl cellulose 36.4 Spray dried lactose 100 Magnesium Stearate 5.2

[0071] The preparation method of the above-mentioned indobufen tablets is as follows:

[0072] Step 1, adding indobufen, ground lactose and magnesium dodecyl sulfate into a mixer hopper, mixing at a speed of 10 rpm for 20 min, then adding into a hammer mill, setting the frequency to 30 Hz, and co-crushing to D90 = 24.2 μm to obtain a co-crushed product;

[0073] Step 2: Add the co-crushed product, microcrystalline cellulose, calcium carboxymethyl cellulose and spray-dried lactose into the mixer hopper, mix at 10 rpm for 20 min, and then add them into the dry granulator for dry granulation. Set the vertical feed speed to 50 Hz, the horizontal feed speed to 120 Hz, the roller speed to 8 rpm, and the oil pump pressure to 6.5 KN. After the granulation, use a 20-mesh screen to dry granulate to obtain granules.

[0074] Step 3: Add additional carboxymethylcellulose calcium to the above granules, mix in a mixer at 10 rpm for 20 min, then add magnesium stearate and continue mixing for 8 min, and use a high-speed tablet press to tablet to obtain indobufen tablets, which are required to have a tablet weight difference of ±5%, a tablet core disintegration time of 3 to 8 min, and a hardness of 100 to 220 N.

[0075] Example 5

[0076] This embodiment provides an indobufen tablet, and the prescription dosage (single tablet dosage) is shown in the following table:

[0077] Components Mass / mg Indobufen 200 Grind lactose 100 Microcrystalline Cellulose 57.6 Add carboxymethylcellulose calcium 26 Magnesium Lauryl Sulfate 5.2 Add calcium carboxymethyl cellulose 26 Spray dried lactose 102.6 Magnesium Stearate 2.6

[0078] The preparation method of the above-mentioned indobufen tablets is as follows:

[0079] Step 1, adding indobufen, ground lactose and magnesium dodecyl sulfate into a mixer hopper, mixing at a speed of 10 rpm for 20 min, then adding into a hammer mill, setting the frequency to 30 Hz, and co-crushing to D90 = 37.3 μm to obtain a co-crushed product;

[0080] Step 2: Add the co-crushed product, microcrystalline cellulose, calcium carboxymethyl cellulose and spray-dried lactose into the mixer hopper, mix at 10 rpm for 20 min, and then add them into the dry granulator for dry granulation. Set the vertical feed speed to 50 Hz, the horizontal feed speed to 120 Hz, the roller speed to 8 rpm, and the oil pump pressure to 6.5 KN. After the granulation, use a 20-mesh screen to dry granulate to obtain granules.

[0081] Step 3: Add additional carboxymethylcellulose calcium to the above granules, mix in a mixer at 10 rpm for 20 min, then add magnesium stearate and continue mixing for 8 min, and use a high-speed tablet press to tablet to obtain indobufen tablets, which are required to have a tablet weight difference of ±5%, a tablet core disintegration time of 3 to 8 min, and a hardness of 100 to 220 N.

[0082] Comparative Example 1

[0083] This comparative example provides an indobufen tablet, and the prescription dosage (single dose) is shown in the following table:

[0084] Components Mass / mg Indobufen 200 Grind lactose 100 Microcrystalline Cellulose 57.6 Magnesium Lauryl Sulfate 5.2 Calcium Carboxymethyl Cellulose 52 Spray dried lactose 100 Magnesium Stearate 5.2

[0085] The preparation method of the above-mentioned indobufen tablets is as follows:

[0086] Step 1, adding indobufen, ground lactose, microcrystalline cellulose, magnesium lauryl sulfate, carboxymethyl cellulose calcium, and spray-dried lactose into the hopper of a mixer, mixing at 10 rpm for 20 min, then adding magnesium stearate and continuing mixing for 8 min to obtain a mixed material;

[0087] Step 2: Compress the above mixed material into tablets using a high-speed tablet press to obtain indobufen tablets, with the tablet weight difference being required to be ±5% and the tablet core disintegration time being 3 to 8 minutes.

[0088] Comparative Example 2

[0089] This comparative example provides an indobufen tablet, and the prescription dosage (single tablet dosage) is shown in the following table:

[0090] Components Mass / mg Indobufen 200 Grind lactose 200 Microcrystalline Cellulose 57.6 Sodium starch glycolate 52 Magnesium Lauryl Sulfate 5.2 Magnesium Stearate 5.2

[0091] The preparation method of the above-mentioned indobufen tablets is as follows:

[0092] Step 1, add indobufen, ground lactose, microcrystalline cellulose, and 1 / 2 of the prescription amount of sodium starch glycolate into a wet granulation mixer, start stirring, stirring speed 250 rpm, shear speed 800 rpm, mix for 5 minutes, then slowly add purified water for wet granulation, stirring speed 250 rpm, shear speed 1800 rpm, granulation for 2 minutes;

[0093] Step 2: Add the obtained particles into a fluidized bed dryer, set the air inlet temperature to 90°C, and dry until the moisture content of the material is less than 3%;

[0094] Step 3, adding the remaining sodium carboxymethyl starch to the wet granulated granules, mixing in a mixer at 10 rpm for 20 min, adding magnesium stearate and continuing to mix for 8 min to obtain a total mixed material;

[0095] Step 4: The total mixed flow is compressed into tablets by a high-speed tablet press to obtain indobufen tablets, the tablet weight difference is required to be ±5%, and the tablet core disintegration time limit is 3 to 8 minutes.

[0096] Comparative Example 3

[0097] This embodiment provides an indobufen tablet, and the prescription dosage (single tablet dosage) is shown in the following table:

[0098] Components Mass / mg Indobufen 200 Grind lactose 100 Microcrystalline Cellulose 57.6 Calcium Carboxymethyl Cellulose 52 Magnesium Lauryl Sulfate 5.2 Spray dried lactose 100 Magnesium Stearate 5.2

[0099] The preparation method of the above-mentioned indobufen tablets is as follows:

[0100] Step 1: Indobufen, ground lactose and magnesium dodecyl sulfate were mixed in a wet granulation mixer at a speed of 10 rpm for 20 minutes; then microcrystalline cellulose, 1 / 2 of the prescribed amount of carboxymethyl cellulose calcium and spray-dried lactose were added, and the mixture was mixed for another 20 minutes;

[0101] Step 2: dry granulate the mixed materials on a dry granulator, set the vertical feed speed to 50 Hz, the horizontal feed speed to 120 Hz, the roller speed to 8 rpm, the oil pump pressure to 6.5 KN, and after granulation, use a 20-mesh screen to dry granulate to obtain granules;

[0102] Step 3, adding the remaining calcium carboxymethyl cellulose to the above-obtained granules, mixing in a mixer at 10 rpm for 20 min, and then adding magnesium stearate and continuing to mix for 8 min;

[0103] Step 4: Use a high-speed tablet press to compress the tablets to obtain indobufen tablets, with the tablet weight difference required to be ±5% and the tablet core disintegration time limit of 3 to 8 minutes.

[0104] Quality Research

[0105] 1. Comparison of tableting process

[0106] The compressibility, sticking, and cracking of the tablets of Examples 1 to 5 and Comparative Examples 1 to 3 during tableting were observed, and the hardness of the prepared indobufen tablets was tested. The results are shown in Table 1.

[0107] Table 1

[0108]

[0109] The results show that the materials prepared in Examples 1 to 5 have good compressibility during the tableting process, and the tablet core hardness is greater, and no sticking or cracking occurs. Comparative Example 1 is prepared using a direct powder tableting process, and the material has extremely poor compressibility, and there are problems such as sticking, low tablet core hardness, and cracking. Comparative Example 2 is prepared using a wet granulation process, and the compressibility is improved compared to direct powder tableting, but sticking occurs in the later stage of tableting, and the tablet surface gloss is insufficient. If the tablet core hardness continues to increase, cracking will occur. The material prepared in Comparative Example 3 has good compressibility during the tableting process, and the tablet core hardness is greater, and no sticking or cracking occurs. That is, the preparation process of the present invention can obtain a material with good compressibility, which solves the problems of poor compressibility, sticking, and low hardness in the product tableting process.

[0110] 2. Dissolution curve detection

[0111] 2.1 Standard medium

[0112] According to the standard provisions under the dissolution test item in the national drug standard for indobufen tablets (WS1-(X-072)-2006Z-2021), the standard medium pH 7.6 phosphate buffer was selected, and the basket method was used at a speed of 75 r / min to investigate the dissolution curves of the indobufen tablets prepared in the above Examples 1 to 5 and Comparative Examples 1 to 3. Under the same conditions, the dissolution curve of the reference preparation (trade name: Ibustrin, specification: 0.2 g; batch number: HC8065) ​​was detected, and the results are shown in Table 2.

[0113] Table 2

[0114]

[0115] Note: f2 greater than 50 indicates similarity to the reference preparation.

[0116] The results show that the dissolution curves of the products prepared in Examples 1 to 5 in the standard medium of indobufen tablets are greater than 50, and the f2 of the reference preparation is greater than 50, indicating that the products in the embodiments of the present invention are similar to the reference preparation. Comparative Example 1 uses powder direct tableting, and the API cannot be well dispersed. The dissolution curve results of the product show that the dissolution rate is significantly reduced, and the similarity with the reference preparation is poor. Comparative Example 2 is prepared by wet granulation technology, and the f2 value of the dissolution curve and the reference preparation is 52. Although similar, the dissolution effect is still insufficient compared with the product of the present invention, and its product has problems such as sticking in the later stage of tableting, insufficient glossiness of the sheet surface, low hardness, and cracking after increasing pressure, which is not conducive to the improvement of product quality and commercial production. In Comparative Example 3, the raw material drug is not co-crushed with ground lactose and internal lubricant, and a material with good compressibility is obtained by dry granulation. Although there are no problems of sticking, cracking, and low hardness, its dissolution rate in the standard medium is low, and the f2 value of the dissolution curve of the reference preparation is lower than 50, which is not similar to the reference preparation.

[0117] 2.2 Acidic medium

[0118] The indobufen tablets prepared in Examples 1 to 5 and Comparative Examples 1 to 3 and the reference preparation were subjected to an in vitro dissolution comparative test in an acidic medium. The paddle method of the 2020 edition of the Chinese Pharmacopoeia General Dissolution Method Method 2 was adopted, the dissolution medium: pH 1.2 hydrochloric acid solution, pH 4.5 acetate buffer, medium volume 900 mL, rotation speed 50 rpm, and the dissolution curve test results are shown in Tables 3 and 4.

[0119] Table 3 Dissolution curve results in pH 1.2 hydrochloric acid medium

[0120]

[0121]

[0122] Table 4 Dissolution curve results in pH 4.5 acetate buffer

[0123]

[0124] The results showed that the dissolution amount of the indobufen tablets prepared in Examples 1 to 5 in a hydrochloric acid medium at pH 1.2 and an acetate buffer at pH 4.5 was significantly higher than that of the reference preparation.

[0125] Compared with the comparative examples, the products of the preparation process of the present invention are subjected to a co-crushing process of the API and the water-soluble excipient lactose and an internal lubricant on the basis of dry granulation, so that the contact specific surface area between the API and the water-soluble excipient is further increased, which is more conducive to the wetting and dissolution of the API. Compared with comparative example 1 (direct powder tableting process) and comparative example 2 (wet granulation process), the dissolution amount of the products prepared by the present invention in the acidic medium has been significantly improved. It can be concluded from the dissolution results of comparative example 3 without co-crushing that the co-crushing process in the embodiment significantly increases the dissolution amount of the product.

[0126] In summary, the embodiment of the present invention uses co-crushing treatment with indobufen, ground lactose, and internal lubricant, controls the D90 particle size of the co-crushed material to be 10-40 μm, then adds spray-dried lactose, microcrystalline cellulose, and internal disintegrant for dry granulation, and finally adds external disintegrant and external lubricant for tableting to prepare indobufen tablets. Through the above process, the prepared material has good compressibility, which solves the problems of sticking, cracking, and low hardness of indobufen during tableting. At the same time, the dissolution level of the prepared indobufen tablets in acidic media is significantly improved, which is more conducive to the clinical effect of the product, thereby being able to replace the original research product; and the preparation production process is simple, easy to realize industrial large-scale production, and has a high value of promotion and application.

[0127] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. An indobufen pharmaceutical composition, characterized in that: comprising indobufen co-crushed material, spray-dried lactose, an external lubricant, a disintegrant and microcrystalline cellulose; The indobufen co-crushed material comprises indobufen, ground lactose and an internally added lubricant.

2. The indobufen pharmaceutical composition according to claim 1, wherein the additional lubricant comprises magnesium stearate; and / or The internal lubricant includes one or both of magnesium lauryl sulfate and sodium lauryl sulfate; and / or The disintegrant is carboxymethylcellulose calcium.

3. The indobufen pharmaceutical composition according to claim 1, characterized in that: The particle size D90 of the indobufen is 10 μm to 60 μm; and / or The particle size D90 of the indobufen co-crushed product is 10 μm to 40 μm; and / or The average particle size of the spray-dried lactose is 75 μm to 200 μm; and / or The average particle size of the ground lactose is 20 μm to 60 μm.

4. The indobufen pharmaceutical composition according to claim 1, characterized in that: The mass ratio of the ground lactose to indobufen is 1:4 to 1:1; the spray-dried lactose accounts for 10% to 30% of the total mass of the indobufen pharmaceutical composition.

5. The indobufen pharmaceutical composition according to claim 4, characterized in that: The mass ratio of the ground lactose to indobufen is 1:2; the spray-dried lactose accounts for 10% to 20% of the total mass of the indobufen pharmaceutical composition.

6. The indobufen pharmaceutical composition according to claim 1, characterized in that: The microcrystalline cellulose accounts for 5% to 20% of the total mass of the indobufen pharmaceutical composition.

7. The indobufen pharmaceutical composition according to claim 1, characterized in that: The internal lubricant accounts for 0.1% to 2% of the total mass of the indobufen pharmaceutical composition, and the external lubricant accounts for 0.25% to 1.5% of the total mass of the indobufen pharmaceutical composition.

8. The indobufen pharmaceutical composition according to claim 1, characterized in that: The disintegrant is 5% to 15% of the total mass of the indobufen pharmaceutical composition.

9. An indobufen tablet, characterized in that: The indobufen pharmaceutical composition is prepared from the indobufen pharmaceutical composition according to any one of claims 1 to 8.

10. A method for preparing the indobufen tablet according to claim 9, characterized in that: The steps include: S1, mixing indobufen, ground lactose and an internal lubricant uniformly, and crushing to obtain indobufen co-crushed material; S2, mixing the indobufen co-crushed material, microcrystalline cellulose, part of the disintegrant and spray-dried lactose uniformly, and dry granulating to obtain granules; S3, mixing the granules with the remaining disintegrant and the external lubricant evenly, and tableting to obtain indobufen tablets.

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