A dry suspension and preparation method thereof

Abstract

The present invention belongs to the field of medical technology, and specifically relates to a dry suspension and a preparation method thereof, wherein the dry suspension comprises the following components in mass percentage: 50-70% of imeglimine; 1-5% of a binder; 20-35% of a diluent; 0.8-2.3% of xanthan gum; 0.2-1.7% of carob bean gum; 0.3-0.7% of a glidant; 0.8-2.0% of an anti-caking agent; and 1.3-1.7% of a pH regulator. The dry suspension of the present invention has high stability and good redispersibility, and has better dissolution and faster dissolution speed than tablets, better tolerance, and is convenient for patients to eat.

Description

Technical Field

[0001] The invention belongs to the technical field of medicine, and particularly relates to a dry suspension and a preparation method thereof. Background Art

[0002] The chemical name of Imeglitin is (6R)-(+)-4-dimethylamino-2-imino-6-methyl-1,2,5,6-tetrahydro-1,3,5-triazine, and the molecular formula is C6H 13 N5, relative molecular mass is 155.2, solubility in water is 4.63 mg / mL.

[0003] Imegliptin is a new type of oral hypoglycemic drug that improves pancreatic beta cell function by targeting mitochondria in the pancreas, muscles and liver, promotes insulin secretion, regulates oxidative stress, and reduces gluconeogenesis, ultimately improving the disease progression of type 2 diabetes.

[0004] The currently marketed imeglimine preparations are tablets with a specification of 500 mg and a tablet size of 17.6 mm*7.1 mm*5.3 mm. The currently marketed tablets are not suitable for patients with dysphagia and have poor patient compliance.

[0005] WO 2011 / 154497 discloses a film-coated tablet containing 83.4% of imeglimine as an oral imeglimine preparation, but does not disclose any practical preparation method thereof.

[0006] WO 2010 / 066326 discloses a tablet containing 87.0% of imeglimine as an oral imeglimine preparation, which is prepared on a 1 kg scale by direct compression, that is, blending the composition components and then compressing. Direct compression is easy for small-scale production, but in the case of enlarging the production scale, the compression time of the powder is shortened, and therefore, when the compression moldability of the drug is poor, tableting failure may occur and tableting may become difficult. Therefore, there is no practical method for stably preparing oral tablets containing imeglimine on a large scale.

[0007] CN 114945370 A discloses a tablet containing 90%-92% imeglimine as an oral imeglimine product, with a specification of 500 mg and a tablet size of 17.6 mm*7.1 mm*5.3 mm. Although the size is smaller than that of commercially available preparations, the compliance of the elderly and children with dysphagia still needs to be improved. Summary of the invention

[0008] Therefore, the present invention aims to overcome the defect that the current imeglimine tablets are difficult to deal with and solve the poor taking properties of elderly people and children with dysphagia, thereby providing a new imeglimine preparation to deal with patients with dysphagia, and using imeglimine to treat diabetes. A dry suspension refers to a powder or granular material made of a poorly soluble drug and suitable excipients, which can be dispersed into a suspension for oral administration by adding water and shaking when in use. After the dry suspension is dispersed with water, the microparticles therein are evenly dispersed and settle slowly, and can be dispersed again by gently shaking after sedimentation. The dry suspension has the characteristics of a solid preparation, which is convenient to carry, easy to transport, and has good stability, and has the advantages of a liquid preparation, which is convenient to take and suitable for patients with dysphagia.

[0009] To this end, the present invention provides a dry suspension and a preparation method thereof, the purpose of which is to improve the difficulty in swallowing of tablets, the gritty mouthfeel produced when chewable tablets and granules are taken, and to improve patient compliance.

[0010] The present invention provides a dry suspension, which comprises the following components by mass percentage, based on the total mass percentage of the dry suspension being 100%:

[0011]

[0012]

[0013] Further, the adhesive is selected from one or more combinations of soybean lecithin, hydroxypropyl cellulose, pregelatinized starch and polyvinyl pyrrolidone; and / or the diluent includes one or more combinations of sorbitol, lactose, microcrystalline cellulose, pregelatinized starch; and / or the suspending agent includes one or more combinations of xanthan gum, carob gum, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, guar gum, gum arabic, tragacanth gum, karaya gum, and gelatin; and / or the glidant includes at least one of colloidal silicon dioxide, talc, and magnesium stearate; and / or the anti-caking agent includes at least one of calcium phosphate and tribasic calcium phosphate; and / or the pH regulator includes an alkaline regulator and an acidic regulator.

[0014] Furthermore, the dry suspension also includes a flavoring agent; preferably, the mass percentage of the flavoring agent to the mass percentage of the dry suspension is 1.6-2.1%.

[0015] Furthermore, the flavoring agent comprises sucrose and / or essence; preferably, the mass percentage of the sucrose to the mass percentage of the dry suspension is 0.4% to 0.6%, and the mass percentage of the essence to the mass percentage of the dry suspension is 1.2% to 1.6%.

[0016] Furthermore, the xanthan gum and carob bean gum are suspending agents; the mass percentage of the xanthan gum in the dry suspension is preferably 1.2% to 2.0%, preferably 2.0%; the mass percentage of the carob bean gum in the dry suspension is preferably 0.5 to 1.2%, preferably 0.5%.

[0017] Furthermore, the acidic regulator includes at least one of anhydrous citric acid and sodium dihydrogen phosphate, and the alkaline regulator includes at least one of sodium citrate and sodium hydrogen phosphate; preferably, the mass percentage of the acidic regulator to the mass percentage of the dry suspension is 0.07% to 0.08%, and the mass percentage of the alkaline regulator to the mass percentage of the dry suspension is 1.3% to 1.6%.

[0018] Furthermore, the binder is soybean lecithin; and / or the diluent is sorbitol; and / or the glidant is silicon dioxide; and / or the anti-caking agent is tribasic calcium phosphate.

[0019] Furthermore, the mass percentage of the imeglimine in the dry suspension is 55% to 70%; and / or the mass percentage of the binder in the dry suspension is 1.2% to 4.2%; and / or the mass percentage of the diluent in the dry suspension is 20.0% to 24.8%; and / or the mass percentage of the glidant in the dry suspension is 0.30% to 0.32%; and / or the mass percentage of the anti-caking agent in the dry suspension is 0.99% to 1.90%.

[0020] The present invention also provides a method for preparing a dry suspension, comprising the following steps: mixing imeglimine, a diluent, xanthan gum, carob bean gum and a flow aid, granulating under the action of a binder and an alkaline regulator, and mixing the obtained granules with an anti-caking agent and an acidic regulator to obtain a dry suspension.

[0021] Furthermore, before mixing, the imeglimine is pulverized, and the particle size D90 of the pulverized material is less than 200 μm, preferably 80 μm≤D90≤120 μm.

[0022] Beneficial effects of the technology of the present invention:

[0023] (1) The dry suspension provided by the present invention comprises the following components by mass fraction: 50-70% of imeglimine, 1-5% of a binder, 20-35% of a diluent, 0.8-2.3% of xanthan gum, 0.2-1.7% of carob bean gum, 0.3-0.7% of a glidant, 0.8-2.0% of an anti-caking agent, and 1.3-1.7% of a pH regulator. The dry suspension is prepared by using imeglimine, a binder, a diluent, xanthan gum, carob bean gum, a glidant, an anti-caking agent, and a pH regulator in combination at specific contents. The dry suspension can be dispersed after adding water, has the characteristics of a solid preparation, is convenient to carry, convenient to transport, and has good stability, and has the advantages of a liquid preparation, is convenient to take, and is suitable for patients with dysphagia.

[0024] (2) The dry suspension provided by the present invention optimizes the mass percentage of each component to control the mass percentage of the imeglimine in the dry suspension to be 64% to 70%; and / or the mass percentage of the binder in the dry suspension to be 1.2% to 4.2%; and / or the mass percentage of the diluent in the dry suspension to be 20.0% to 24.8%; and / or the mass percentage of the glidant in the dry suspension to be 0.30% to 0.32%; and / or the mass percentage of the anti-caking agent in the dry suspension to be 0.99% to 1.90%, so that the dry suspension can reduce the radius of the imeglimine particles, more significantly reduce the sedimentation rate, further improve the stability of the suspension, and also effectively improve the gravel-like mouthfeel, making it more convenient and smooth to take, and having high patient compliance.

[0025] (3) The dry suspension provided by the present invention adopts a suspending agent comprising xanthan gum and carob bean gum; wherein the mass percentage of xanthan gum in the dry suspension is 1.2% to 2.0%, preferably 2.0%; the mass percentage of carob bean gum in the dry suspension is 0.5 to 1.2%, preferably 0.5%. The xanthan gum and carob bean gum at this mass percentage can not only achieve the suspending effect, but also significantly reduce the sedimentation rate, further improve the stability of the suspension, and alleviate the diarrhea problem generated during the administration process, and have good safety. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] In order to more clearly illustrate the specific implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0027] Figure 1It is the drug-time curve of Example 2 and Comparative Example 10 in Experimental Example 3, wherein the horizontal axis is the average blood drug concentration and the vertical axis is time. DETAILED DESCRIPTION

[0028] In order to further illustrate the present invention, the following is a detailed description of an imeglitinide method provided by the present invention in conjunction with the examples, but it should not be understood as limiting the scope of protection of the present invention. If no specific experimental steps or conditions are specified in the examples, the conventional experimental steps or conditions described in the literature in the field can be used. If the manufacturer of the reagents or instruments used is not specified, they are all conventional reagent products that can be purchased commercially.

[0029] Among them, soybean lecithin was purchased from Shanghai Taiwei Pharmaceutical Co., Ltd. and mixed fruit flavor was purchased from Senxin Flavor and Color Technology (China) Co., Ltd.

[0030] Examples 1-6 provide a series of dry suspensions, and the formulations are shown in Table 1.

[0031] Table 1 Prescription table of Examples 1-6 (1000 preparation units)

[0032]

[0033] The preparation method is as follows:

[0034] (1) Raw material pretreatment: The particle size of the imeglitinide raw material was crushed to 80 μm ≤ D90 ≤ 120 μm using a jet mill;

[0035] (2) Premixing: sorbitol is passed through a 20-mesh sieve, and then mixed with imeglimine, colloidal silicon dioxide, xanthan gum, and carob bean gum, and mixed well for later use;

[0036] (3) Granulation: dispersing soybean lecithin in ethanol to obtain an ethanol solution of soybean lecithin, dissolving sodium citrate in water to obtain an aqueous solution of sodium citrate, mixing the ethanol solution of soybean lecithin and the aqueous solution of sodium citrate to obtain a mixed solution, using the mixed solution as a binder to place the mixed powder in (2) in a wet granulation pot for wet granulation to obtain granules;

[0037] (4) Mixing: Mix the medium granules in (3) with fruit essence, tribasic calcium phosphate, anhydrous citric acid, and sucrose;

[0038] (5) Packaging: Use a packing machine for packaging, each bag contains 1 g of imeglitinide.

[0039] Example 7 provides a dry suspension, the formula of which is shown in Table 2.

[0040] Table 2 Prescription table of Example 7 (1000 preparation units)

[0041]

[0042] The preparation method is the same as that of Example 1, the only difference being that in this example, the "sorbitol" in Example 1 is replaced by "microcrystalline cellulose" and "lactose".

[0043] Examples 8-15 provide a series of dry suspensions, and the formulations are shown in Table 3.

[0044] Table 3 Prescription table of Examples 8-15 (1000 preparation units)

[0045]

[0046]

[0047] The preparation method is the same as that of Example 1.

[0048] Example 16 provides a dry suspension, the formulation of which is shown in Table 4.

[0049] Table 4 Prescription table of Example 16 (1000 preparation units)

[0050]

[0051] The preparation method is as follows:

[0052] (1) Raw material pretreatment: The particle size of the imeglitinide raw material is crushed to the corresponding requirement (120 μm ≤ D90 ≤ 200 μm) by a jet mill;

[0053] (2) Premixing: sorbitol is passed through a 20-mesh sieve, and then mixed with imeglimine, colloidal silicon dioxide, xanthan gum, and carob bean gum, and mixed well for later use;

[0054] (3) Granulation: dispersing soybean lecithin in ethanol to obtain an ethanol solution of soybean lecithin, dissolving sodium citrate in water to obtain an aqueous solution of sodium citrate, mixing the ethanol solution of soybean lecithin and the aqueous solution of sodium citrate to obtain a mixed solution, using the mixed solution as a binder to place the mixed powder in (2) in a fluidized bed for wet granulation.

[0055] (4) Mixing: Mixing the medium granules in (3) with mixed fruit essence, tribasic calcium phosphate, citric acid, and sucrose;

[0056] (5) Packaging: Use a packaging machine for packaging, each bag contains 1 g of imeglitinide.

[0057] Comparative Examples 1-5 provide a series of dry suspensions, and the formulations are shown in Table 5.

[0058] Table 5 Prescription table of comparative examples 1-5 (1000 preparation units)

[0059]

[0060]

[0061] The preparation method is the same as that in Example 1, except that in Comparative Example 1, "xanthan gum and carob bean gum" in Example 1 are replaced with "xanthan gum". In Comparative Example 2, "xanthan gum and carob bean gum" in Example 1 are replaced with "carob bean gum", in Comparative Example 3, "xanthan gum and carob bean gum" in Example 1 are replaced with "arabic gum", in Comparative Example 4, "xanthan gum and carob bean gum" in Example 1 are replaced with "Karayuga gum", and in Comparative Example 5, "xanthan gum and carob bean gum" in Example 1 are replaced with "guar gum".

[0062] Comparative Examples 6-9 provide a series of dry suspensions, and the formulations are shown in Table 6.

[0063] Table 6 Prescription table of comparative examples 6-9 (1000 preparation units)

[0064]

[0065] The preparation method is the same as that of Example 1.

[0066] Comparative Example 10 provides a tablet, wherein the mass of imeglimine in each tablet is 500 mg, that is, the specification of imeglimine tablet is 500 mg, and the formula is shown in Table 7.

[0067] Table 7 Prescription of Imeglimine Tablets (1000 dosage units)

[0068]

[0069]

[0070] The preparation method is as follows:

[0071] (1) Raw material pretreatment: The particle size of the imeglitinide raw material is crushed to the corresponding requirement (120 μm ≤ D 90 ≤200μm);

[0072] (2) Premixing: sorbitol is passed through a 20-mesh sieve, and then mixed with imeglimine and colloidal silicon dioxide, and the mixture is mixed and set aside;

[0073] (3) Granulation: dispersing soybean lecithin in ethanol to obtain an ethanol solution of soybean lecithin, dissolving sodium citrate in water to obtain an aqueous solution of sodium citrate, mixing the ethanol solution of soybean lecithin and the aqueous solution of sodium citrate to obtain a mixed solution, using the mixed solution as a binder to place the mixed powder in (2) in a fluidized bed for wet granulation.

[0074] (4) Blending: Blend the granules in (3) with sodium carboxymethyl cellulose, anhydrous citric acid, sucrose and magnesium stearate, and compress the mixture into tablets.

[0075] Comparative Example 11 provides a tablet, wherein the mass of imeglimine in each tablet is 500 mg, that is, the specification of imeglimine tablet is 500 mg, and the formula is shown in Table 8.

[0076] Table 8 Prescription of Imeglimine Tablets (1000 dosage units)

[0077]

[0078] The preparation method is the same as that of Comparative Example 10, the only difference being that in this Comparative Example, the "sorbitol" in Comparative Example 10 is replaced by "microcrystalline cellulose" and "lactose".

[0079] Experimental Example 1 Quality Evaluation

[0080] The sedimentation volume ratio and redispersibility of the dry suspension prepared in each of Examples 1 to 16 and Comparative Examples 1 to 9 were tested. (Prescription screening was performed based on the comprehensive results of sedimentation volume ratio and redispersibility.)

[0081] According to the requirements of the fourth general rules for oral suspensions in the 2020 edition of the Chinese Pharmacopoeia, the sedimentation volume ratio of the dry suspension prepared in each embodiment and comparative example was tested. Sedimentation volume ratio detection method: Take a single preparation unit of the test sample, add water to make a suspension containing 20g·L imeglitinide. -1 After mixing, pour the suspension into a 50 ml stoppered measuring cylinder. After vigorous shaking for 1 min, record the initial height H0. Record the height H after standing for 3 hours and 30 days. The higher the sedimentation volume ratio H / H0, the more stable the suspension.

[0082] Take a single unit of the test product and add water to make a solution containing 20 g·L of imeglitinide. -1 The suspension was mixed and poured into a 10 ml stoppered graduated cylinder. After vigorous shaking for 1 min, it was placed at room temperature. The 10 ml stoppered graduated cylinder containing the suspension that had been placed for several days was rotated 180 degrees, inverted once and stopped for 5 seconds, recorded as shaking once, and the number of shakings when it was redispersed into a uniform system was recorded. The fewer the number of shakings, the easier it is to disperse the dry suspension, and the better the redispersibility. Wherein # represents the number of shakings of 1-4 times, ## represents the number of shakings of 5-8 times, ### represents the number of shakings of 9-12 times, #### represents the number of shakings of 13-16 times, ##### represents the number of shakings of 17-20 times, and ###### represents that it is still unable to disperse after shaking 25 times, and the shaking is terminated.

[0083] Table 9 Sedimentation volume ratio and redispersibility results of Examples 1-16 and Comparative Examples 1-9

[0084]

[0085]

[0086] By comparing the sedimentation volume ratio and redispersibility of Examples 1-16 with Comparative Examples 1-9, it is shown that the present invention uses xanthan gum and carob bean gum in combination as suspending agents to achieve good results, while the sedimentation volume ratio or redispersibility of the dry suspension prepared by using xanthan gum or carob bean gum alone or using other suspending agents alone is poor. Comparative Example 1 has very poor redispersibility and cannot be dispersed by shaking; the sedimentation volumes of Comparative Examples 2-9 are all lower than 0.8, and the 30-day stability of the suspension is significantly reduced. The present invention further investigates the dosage of xanthan gum and carob bean gum. The 3h sedimentation volume ratio of the dry suspension added with 0.8-2.3% xanthan gum and 0.2-1.7% carob bean gum is higher than 0.8, and the sedimentation volume ratio after 30 days is higher than 0.6, and there is no situation that it cannot be dispersed after shaking, which is significantly better than other dry suspensions in Comparative Examples 6-9.

[0087] Comparison between Example 2 and Example 7 shows that the present invention can further improve the redispersibility and stability of the dry suspension by optimizing the type of diluent.

[0088] Comparison of Example 2 with Examples 3-6 shows that the present invention can further improve the redispersibility and stability of the dry suspension by limiting the mass percentages of the diluent, the glidant, the binder, and the anti-caking agent within the preferred range.

[0089] Experimental Example 2 Dissolution

[0090] The dry suspension of Example 1 (1 bag) and Example 2 (1 bag), the tablets of Comparative Example 10 (1 tablet) and Comparative Example 11 (1 tablet) were tested for dissolution (n=6). (The dissolution medium was acetic acid-sodium acetate solution with a pH of 4.5, 900 ml, and the paddle method was used for testing).

[0091] Table 10 Example 1-2 Dry Suspension Comparative Example 1-2 Imeglitinide Tablet Dissolution

[0092]

[0093] By comparing the dissolution rates of Example 2 with those of Example 1 and Comparative Examples 1-2, it is shown that the dissolution rates of the dry suspensions and tablets prepared by Examples 1 and 2 of the present invention within 2 hours meet the requirements of the Chinese Pharmacopoeia and have good stability. Compared with tablets, the prepared dry suspensions can increase the dissolution rate and dissolution rate of the drug, and are expected to achieve rapid limiting dissolution in the in vivo environment.

[0094] Experimental Example 3 In vivo PK study

[0095] The dry suspension was prepared according to the method of Example 2, and the tablets were prepared according to the method of Comparative Example 10. The dry suspension of Example 2 and the tablets of Comparative Example 10 were respectively added with water to prepare a mixture containing 20 g·L imeglitinide. -1 of solution and mix well. 60 healthy Wistar rats (weight 180-210g) were randomly divided into two groups, 30 rats in each group. Rats were not allowed to fast or drink water before the experiment, and the dose was 5mg / kg. Venous blood was collected before administration (0h) and 5min, 10min, 20min, 30min, 45min, 60min, 75min, 90min, 120min, 180min, 240min, 300min, 360min and 720min after administration, and the plasma was separated and stored at -20℃ for testing. The drug concentration in plasma was determined by LC-MS / MS, and the results were analyzed using CPhaMAS software. The results are as shown in Figure 1 As shown, the PK parameters are shown in Table 11. From the PK parameters, it can be seen that Example 2 can enter the body and quickly exert its therapeutic effect, AUC INF_obs ,AUC last All are greater than Comparative Example 10.

[0096] Table 11 PK parameters of Example 2 and Comparative Example 10

[0097]

[0098] Experimental Example 4 Safety Evaluation

[0099] The three groups of rats after the in vivo PK study of Experimental Example 3 were rated for safety, and whether the rats had diarrhea was determined by whether watery stools and mucous stools appeared. The number of cases of diarrhea after rats took Comparative Example 10 was 2, and the diarrhea rate was 6.6%. No rats taking Example 2 had diarrhea. Therefore, the dry suspension of Example 2 has better tolerance than the tablets of Comparative Example 10.

Claims

1. A dry suspension, characterized in that: Taking the total mass of the dry suspension as 100%, the dry suspension comprises the following components by mass fraction: Imeglistin 50-70%; Adhesive 1-5%; Diluent 20-35%; Xanthan gum 0.8-2.3%; Carob bean gum 0.2-1.7%; Flow aid 0.3-0.7%; Anti-caking agent 0.8-2.0%; pH adjuster 1.3-1.7%; The binder is selected from soybean lecithin; The diluent is selected from one or a combination of sorbitol, lactose, and microcrystalline cellulose; The glidant is selected from colloidal silicon dioxide; The anti-caking agent is selected from tribasic calcium phosphate; The pH regulator comprises an alkaline regulator and an acidic regulator; The acidic regulator includes at least one of anhydrous citric acid and sodium dihydrogen phosphate, and the alkaline regulator includes at least one of sodium citrate and sodium hydrogen phosphate.

2. The dry suspension according to claim 1, characterized in that The dry suspension may also include a flavoring agent.

3. The dry suspension according to claim 2, characterized in that The mass percentage of the flavor corrective to the mass percentage of the dry suspension is 1.6-2.1%.

4. The dry suspension according to claim 2, characterized in that The flavoring agent comprises sucrose and / or essence.

5. The dry suspension according to claim 4, characterized in that The mass percentage of the sucrose in the dry suspension is 0.4% to 0.6%; the mass percentage of the flavor in the dry suspension is 1.2% to 1.6%.

6. The dry suspension according to claim 1, characterized in that The mass percentage of the xanthan gum in the dry suspension is 1.2% to 2.0%; the mass percentage of the carob bean gum in the dry suspension is 0.5% to 1.2%.

7. The dry suspension according to claim 6, characterized in that The mass percentage of the xanthan gum in the dry suspension is 2.0%; the mass percentage of the carob bean gum in the dry suspension is 0.5%.

8. The dry suspension according to claim 1, characterized in that The mass percentage of the acidic regulator to the dry suspension is 0.07% to 0.08%; the mass percentage of the alkaline regulator to the dry suspension is 1.3% to 1.6%.

9. The dry suspension according to claim 1, characterized in that The diluent is sorbitol.

10. The dry suspension according to any one of claims 1 to 9, characterized in that The mass percentage of the imeglimine in the dry suspension is 55%-70%; and / or the mass percentage of the binder in the dry suspension is 1.2%-4.2%; and / or the mass percentage of the diluent in the dry suspension is 20.0%-24.8%; and / or the mass percentage of the glidant in the dry suspension is 0.30%-0.32%; and / or the mass percentage of the anti-caking agent in the dry suspension is 0.99%-1.90%.

11. A method for preparing the dry suspension according to any one of claims 1 to 10, characterized in that: The method comprises the following steps: mixing imeglimine, a diluent, xanthan gum, carob bean gum and a flow aid, granulating under the action of a binder and an alkaline regulator, and mixing the obtained granules with an anti-caking agent and an acidic regulator to obtain a dry suspension.

12. The method for preparing the dry suspension according to claim 11, characterized in that: Before mixing, the imeglimine is pulverized, and the particle size D90 of the imeglimine after pulverization is less than 200 μm.

13. The method for preparing the dry suspension according to claim 12, characterized in that: The particle size D90 of the imipramine after pulverization is 80 μm≤D90≤120 μm.

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