A kind of tranexamic acid pharmaceutical composition and preparation process thereof

Abstract

The present invention belongs to the technical field of pharmaceutical preparations, and provides a tranexamic acid pharmaceutical composition and a preparation process thereof. The tranexamic acid pharmaceutical composition is prepared by a fluidized bed granulation process using tranexamic acid, povidone, calcium bicarbonate dihydrate, cross-linked sodium carboxymethyl cellulose, colloidal silicon dioxide, magnesium stearate and oil-based lubricating auxiliary materials as raw materials; the oil-based lubricating auxiliary materials are selected from at least one of distearic acid glyceryl, behenic acid glyceryl and hydrogenated castor oil. The present invention solves the problem of rapid dissolution and release of tranexamic acid drugs, and can reduce the irritation to the gastrointestinal tract; at the same time, it also improves the stickiness and astringency problems generated during tableting; and the process operation is simple, the production efficiency is high, and it is conducive to industrial production; it is consistent with the quality of the reference preparation, and the clinical substitutability of the reference preparation is achieved, the price is lower, and the accessibility is high.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations and provides a tranexamic acid pharmaceutical composition and a preparation process thereof. Background Art

[0002] Tranexamic acid, also known as tranexamic acid and tranexamic acid, is an antifibrinolytic agent that can inhibit the effects of plasmin activators and plasminogen. It has a hemostatic effect in bleeding associated with increased fibrinolysis, as well as anti-allergic and anti-inflammatory effects due to the inhibition of the formation of kinins and other active peptides involved in allergic and inflammatory reactions. It has been widely used in clinical practice in China and is included in the new edition of the Chinese Pharmacopoeia.

[0003] Chinese invention patent application CN102525878A and CN104414991A both disclose a kind of tranexamic acid tablet and preparation method thereof, and obtain by wet granulation, dry granulation or melt granulation process granulation and then tabletting.But because the raw material medicine accounts for a large proportion in the prior art, the auxiliary material accounts for a small proportion, and the main drug property has a great influence on the dissolution of the final tablet, the property of the prepared preparation mostly depends on the raw material medicine property, and the sticky and astringent punch of tranexamic acid tabletting alone is serious, and it is impossible to form, and the compressibility and fluidity of the raw material and auxiliary material mixed powder are poor, causing the tablet weight difference to be easily over-limited, and easily causing the drug content uniformity to be unqualified.And the granulation process will also have a significant impact on the quality of the tranexamic acid tablets finally made, and the preparation process of the prior art is mostly wet granulation, and the process has a great influence on dissolution, and it is also difficult to control the particle size distribution, which is very easy to cause the phenomenon of excessive friability and large tablet weight difference during tabletting. In addition, tranexamic acid is a highly soluble drug that is released quickly in the body but absorbed slowly. It can easily irritate the stomach and cause adverse reactions such as nausea, vomiting, and heartburn.

[0004] Therefore, under the premise of ensuring the quality of the drug, selecting appropriate excipients and new preparation processes to control the dissolution of tranexamic acid tablets while improving bioavailability can solve problems such as large differences in tablet weight, excessive friability, and stickiness and astringency during tableting, which has positive significance for ensuring the efficacy and safety of clinical medication. Summary of the invention

[0005] The present invention aims at the problems existing in the prior art and provides a tranexamic acid pharmaceutical composition and a preparation process thereof. The present invention solves the problem of rapid dissolution and release of tranexamic acid drugs by optimizing the prescription and process, reduces the irritation to the gastrointestinal tract, and improves the problems of stickiness and astringency generated during tableting. The process operation is simple, the production efficiency is high, and it is conducive to industrial production; the quality is consistent with the reference preparation and it is bioequivalent to it in vivo, so it can be clinically replaced by the reference preparation, and the price is lower and the accessibility is high.

[0006] The technical solution of the present invention is as follows:

[0007] The invention provides a tranexamic acid pharmaceutical composition. The raw and auxiliary materials of the tranexamic acid pharmaceutical composition comprise: tranexamic acid, povidone, calcium hydrogen carbonate dihydrate, cross-linked sodium carboxymethyl cellulose, colloidal silicon dioxide, magnesium stearate and oil-based lubricating auxiliary materials.

[0008] Furthermore, the composition of the raw materials and auxiliary materials, measured by weight, includes: 100-120 parts of tranexamic acid, 5-8 parts of povidone, 3-7 parts of calcium bicarbonate dihydrate, 2-4 parts of cross-linked sodium carboxymethyl cellulose, 2-5 parts of colloidal silicon dioxide, 1-3 parts of magnesium stearate and 2-4 parts of oil-based lubricating auxiliary materials.

[0009] Preferably, the composition of the raw materials and auxiliary materials, by weight, includes: 100 parts of tranexamic acid, 5 parts of povidone, 6 parts of calcium bicarbonate dihydrate, 3 parts of cross-linked sodium carboxymethyl cellulose, 2 parts of colloidal silicon dioxide, 1 part of magnesium stearate and 3 parts of oil-based lubricating auxiliary materials.

[0010] Furthermore, the oil-based lubricating auxiliary material is selected from at least one of glyceryl distearate, glyceryl behenate and hydrogenated castor oil; preferably hydrogenated castor oil.

[0011] In some embodiments of the present invention, the raw material composition includes: tranexamic acid, povidone, calcium bicarbonate dihydrate, cross-linked sodium carboxymethyl cellulose, colloidal silicon dioxide, magnesium stearate and glyceryl distearate.

[0012] In some embodiments of the present invention, the raw material composition includes: tranexamic acid, povidone, calcium bicarbonate dihydrate, cross-linked sodium carboxymethyl cellulose, colloidal silicon dioxide, magnesium stearate and glyceryl behenate.

[0013] In some embodiments of the present invention, the raw material composition includes: tranexamic acid, povidone, calcium bicarbonate dihydrate, cross-linked sodium carboxymethyl cellulose, colloidal silicon dioxide, magnesium stearate and hydrogenated castor oil.

[0014] Furthermore, the tranexamic acid pharmaceutical composition is prepared by a fluidized bed granulation process.

[0015] The present invention also provides a preparation process of the above-mentioned tranexamic acid pharmaceutical composition, which specifically comprises the following steps:

[0016] (1) Preheating: Add tranexamic acid and calcium hydrogen phosphate dihydrate into a fluidized bed granulator, mix well, and preheat;

[0017] (2) dissolving povidone in water to obtain a povidone solution;

[0018] (3) spraying a povidone solution and drying to obtain dry granules;

[0019] (4) adding cross-linked sodium carboxymethyl cellulose and colloidal silicon dioxide to the dry granules and mixing evenly, and then adding magnesium stearate and a lubricating auxiliary material such as oil and fat and mixing evenly to obtain a total mixed granule;

[0020] (5) The total mixed granules are compressed into tablets.

[0021] Furthermore, in step (1), the preheating temperature is 50±5°C.

[0022] Furthermore, in step (2), the mass concentration of the povidone solution is 2-10%.

[0023] Furthermore, in step (3), the polyvidone solution is sprayed by top spraying or side spraying.

[0024] Furthermore, in step (3), the injection rate is 7-15 mL / min, the material temperature is 25-35° C.; the drying temperature is 60° C., and the drying end point LOD is less than 1.0%.

[0025] Furthermore, in step (5), the tableting standards are: disintegration time > 10 min, tablet weight difference ≤ 5%, friability ≤ 0.8% and hardness value 50-70N.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] (1) The tranexamic acid pharmaceutical composition of the present invention uses a grease-based lubricating excipient such as glyceryl distearate, glyceryl behenate or hydrogenated castor oil, preferably hydrogenated castor oil, to give play to the combined effects of the grease-based lubricating excipient and calcium hydrogen phosphate dihydrate, and by controlling the dosage ratio of the grease-based lubricating excipient and calcium hydrogen phosphate dihydrate, the problem of rapid dissolution and release of tranexamic acid due to its high water solubility can be solved synergistically, thereby alleviating the irritation to the gastrointestinal tract; at the same time, as a lubricant in the prescription, the combination of the tranexamic acid and magnesium stearate can also solve the problems of stickiness and astringency generated during the tableting process of the tranexamic acid combination.

[0028] (2) In the tranexamic acid pharmaceutical composition of the present invention, colloidal silicon dioxide can be used to make the tablet surface more delicate, and its lubricity can reduce the friction of the mucosa of the medicine cavity, reduce the discomfort of the mouth feel, and effectively improve the swallowability and chewability of large-sized tablets; at the same time, by controlling the amount of colloidal silicon dioxide within a suitable range, the compression resistance and fluidity of the prescription can be significantly improved, so that the tablets compressed in the tableting process can achieve higher hardness, thereby improving the mechanical properties of the drug.

[0029] (3) The present invention adopts a fluidized bed granulation process to prepare tranexamic acid drugs. Compared with the wet granulation process, the one-step granulation process produces a total mixed granule with good compressibility and uniformity, solves the problems of tablet weight difference and sticking phenomenon in production, and has high feasibility; at the same time, the operation is simple, the production efficiency is high, and it is conducive to industrial production.

[0030] (4) The tranexamic acid tablets provided by the present invention slowed down their dissolution rate when accelerated at 60°C and 75% RH for 7 days or at 40°C and 75% RH for 3-6 months, which effectively solved the stability and dissolution problems of the tranexamic acid tablets. The tablets were of the same quality as the reference preparation, and the reference preparation was clinically replaceable, with lower cost and high accessibility. DETAILED DESCRIPTION

[0031] The following non-limiting examples can enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way. The following content is merely an exemplary description of the scope of the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, which should also fall within the scope of the present invention.

[0032] The reference preparation tranexamic acid tablets of the present invention were purchased from Ali Health Pharmacy Medical Chain Co., Ltd., with a specification of 500 mg; the tablet components included calcium carboxymethylcellulose, polyvinyl alcohol, magnesium stearate, hypromellose, polyethylene glycol 6000, talc, titanium dioxide, dimethylpolysiloxane, silicon dioxide, and carnauba wax.

[0033] Example 1

[0034] The prescription of the tranexamic acid pharmaceutical composition of the present embodiment is as follows:

[0035]

[0036] Note: / indicates no additive, the same below.

[0037] Prescription 1-10 adopts fluidized bed granulation process as follows:

[0038] Preheating: Add tranexamic acid and calcium hydrogen phosphate dihydrate (not added in prescriptions 8-10) according to the prescribed amount into the fluidized bed granulator for airflow mixing, preheat for 10 minutes, and set the air inlet temperature to 50±5℃;

[0039] Spraying: Spray the adhesive polyvidone solution (the mass concentration of the polyvidone solution is 2%), the spraying speed is controlled at 15mL / min, and the material temperature is controlled at 25°C; after the spraying is completed, set the air inlet temperature to 60°C for drying, and the drying end point LOD is less than 1.0%;

[0040] The dry granules were passed through a 20-mesh sieve, and then mixed with cross-linked sodium carboxymethyl cellulose and colloidal silicon dioxide for 10 minutes. Magnesium stearate (in the preparation process of prescriptions 4-10, sodium stearyl fumarate, glyceryl distearate, glyceryl behenate or hydrogenated castor oil were added to the magnesium stearate according to the prescription amount) was added to a three-dimensional mixer and mixed for 5 minutes to obtain the total mixed granules;

[0041] A standard rotary tablet press is used to calculate the tablet weight according to the theoretical weight, adjust the pressure, and control the hardness of the tablets to obtain tranexamic acid composition tablets (the tableting standards are as follows: disintegration time > 10 minutes, tablet weight difference ≤ 5%, friability ≤ 0.8%, and hardness value controlled at 50-70N).

[0042] Test Example 1

[0043] The tranexamic acid composition tablets of the above prescriptions 1-6 were subjected to quality testing, and the results are shown in the following table:

[0044]

[0045] The stickiness and astringency during tableting are shown in the following table:

[0046] Tablet Compression Prescription 1 The tablets are sticky and astringent during compression, and continuous compression is impossible. Prescription 2 There are sticky and astringent phenomena, the hardness of the plain tablets is relatively small, and there is a phenomenon of cracking when pressing high hardness Prescription 3 There is a slight stickiness and astringency, and the tablets are relatively hard, but compared with prescription 1 and prescription 2, there is an improvement. Prescription 4 There is a slight stickiness and astringency, but it is improved compared with prescriptions 1 and 2. Prescription 5 Continuous tableting, no sticking or astringent phenomenon Prescription 6 Continuous tableting, no sticking or astringent phenomenon Prescription 7 Continuous tableting, no sticking or astringent phenomenon Prescription 8 Slightly sticky and astringent, the tablet is relatively hard Prescription 9 Slightly sticky and astringent, the tablet is relatively hard Prescription 10 Slightly sticky and astringent, the tablet is relatively hard

[0047] The above results show that: Prescription 1 has obvious stickiness and astringency during tableting and cannot be tableted continuously, which may be caused by the excessively high content of calcium hydrogen phosphate dihydrate; Prescriptions 2-4 increase the content of magnesium stearate or use sodium stearyl fumarate in combination but still cannot meet the product lubrication requirements, and in Prescription 3, over-lubrication occurs, that is, the disintegration time of the tablets is delayed as the tableting process proceeds; Prescriptions 5-7 use fat-soluble lubricants such as distearic acid glyceryl, behenic acid glyceryl or hydrogenated castor oil in combination with magnesium stearate to counteract the stickiness and astringency of tranexamic acid and ensure a smooth tableting process; in addition, Prescriptions 8-10 have poor tableting effects due to the lack of the addition of calcium hydrogen phosphate dihydrate.

[0048] Test Example 2

[0049] The dissolution curves of the tranexamic acid composition tablets of the above prescriptions 2-10 and the reference preparation were tested in a pH 1.2 medium under accelerated conditions (60° C., 75% RH). The results are shown in the following table:

[0050]

[0051] As can be seen from the above table, formulas 5-7 using fat-soluble lubricants (glyceryl distearate, glyceryl behenate or hydrogenated castor oil) and calcium hydrogen phosphate dihydrate as fillers, both as water-insoluble excipients, can effectively coordinate and regulate the dissolution and release of tranexamic acid, compared with formulas 8-10 using fat-soluble excipients alone or formulas 1-3 using calcium hydrogen phosphate dihydrate alone, to achieve a dissolution level similar to or even better than the reference preparation (similarity factor f2>80). Formulas 8-10 using fat-soluble excipients alone or formulas 1-3 using calcium hydrogen phosphate dihydrate alone have faster dissolution and release than the reference preparation, and are not similar.

[0052] Since the f2 of the above prescriptions 2, 3, 4, 8, 9, and 10 at 0 days was less than 50, they were not similar to the reference preparations. Therefore, the dissolution curves of prescriptions 5-7 were further tested with the reference preparations under accelerated conditions (40°C, 75% RH) in a pH 1.2 medium. The results are shown in the following table:

[0053]

[0054]

[0055] It can be seen from the above table that after acceleration under 40°C and 75% RH conditions, the dissolution rates of Prescriptions 5 and 6 slowed down to varying degrees, while the dissolution curves of the reference preparation and Prescription 7 using hydrogenated castor oil were more stable under accelerated conditions, and Prescription 7 was preferred.

[0056] Example 2

[0057] The prescription of the tranexamic acid pharmaceutical composition of the present embodiment is as follows:

[0058]

[0059] (1) The fluidized bed granulation process of prescriptions 11 and 12 is as follows:

[0060] Preheating: Add tranexamic acid, calcium hydrogen phosphate dihydrate and hydrogenated castor oil into the fluidized bed granulator according to the prescribed amount, set the air inlet temperature to 50℃±5℃, and perform air flow mixing for 10 minutes;

[0061] Spraying: Spray the adhesive polyvidone solution (the mass concentration of the polyvidone solution is 10%), the spraying speed is controlled at 7mL / min, and the material temperature is controlled at 35°C; after the spraying is completed, set the air inlet temperature to 60°C for drying, and the drying end point LOD is <1.0%;

[0062] The dry granules were passed through a 20-mesh sieve, and then mixed with colloidal silicon dioxide and cross-linked sodium carboxymethyl cellulose for 10 minutes, and then magnesium stearate and hydrogenated castor oil were added to a three-dimensional mixer and mixed for 5 minutes to obtain the total mixed granules;

[0063] A standard rotary tablet press is used to calculate the tablet weight according to the theoretical weight, adjust the pressure, and control the hardness of the tablets to obtain tranexamic acid composition tablets (the tableting standards are as follows: disintegration time > 10 minutes, tablet weight difference ≤ 5%, friability ≤ 0.8%, and hardness value controlled at 50-70N).

[0064] (2) The high shear wet granulation process of prescriptions 13 and 14 is as follows:

[0065] Add tranexamic acid, calcium hydrogen phosphate dihydrate and hydrogenated castor oil according to the prescription amount into a high-efficiency mixing granulator, and stir and mix for 5 minutes; add a binder polyvidone solution (the mass concentration of the polyvidone solution is 5%), and the liquid addition time is 3 minutes. After the liquid addition is completed, stir and granulate for 3 minutes; after granulation, wet granulate and pass through a 20-mesh screen;

[0066] After granulation, the air inlet temperature was set at 60°C for drying, and the drying end point LOD was less than 1.0%;

[0067] The dry granules were passed through a 20-mesh sieve, and then mixed with colloidal silicon dioxide and cross-linked sodium carboxymethyl cellulose for 10 minutes, and then magnesium stearate and hydrogenated castor oil were added to a three-dimensional mixer and mixed for 5 minutes to obtain the total mixed granules;

[0068] A standard rotary tablet press is used to calculate the tablet weight according to the theoretical weight, adjust the pressure, and control the hardness of the tablets to obtain tranexamic acid composition tablets (the tableting standards are as follows: disintegration time > 10 minutes, tablet weight difference ≤ 5%, friability ≤ 0.8%, and hardness value controlled at 50-70N).

[0069] Test Example 3

[0070] The powder properties of the total mixed particles of the tranexamic acid composition of the above prescriptions 11-14 were tested, and the results are shown in the following table:

[0071]

[0072]

[0073] From the table above, we can see that the particle size distribution of the total mixed granules obtained by the fluidized bed granulation process for prescriptions 11 and 12 is mainly concentrated in 250μm-600μm, and less fine powder is produced than 180μm; while the total mixed granules obtained by the high shear wet granulation process for prescriptions 13 and 14 have more coarse particles greater than 600μm and more fine powder less than 250μm; therefore, the particle size distribution obtained by the fluidized bed granulation process is more uniform and has better fluidity than the high shear wet granulation process. Under the same amount of binder, if the amount of water added in the granulation is too little, the binder is sticky and difficult to disperse evenly. Moreover, the raw materials are highly water-soluble drugs, and the granulation is prone to over-wetting if too much water is added. In the wet granulation process of prescriptions 13 and 14, it is easy to stick to the screen and the particle size is large, which is not conducive to the subsequent tableting process.

[0074] Test Example 4

[0075] The quality of the tranexamic acid composition tablets of the above prescriptions 11-14 was tested, and the results are shown in the following table:

[0076]

[0077] From the above table, it can be seen that: Prescriptions 11 and 12 use fluidized bed granulation technology, which can tolerate higher granulation water addition at high binder dosage, resulting in lower binder concentration, easier to disperse evenly in the prescription, better granulation uniformity, better process smoothness than high shear wet granulation technology, less equipment is used in preparation, and the prepared total mixed granules are better than prescriptions 13 and 14 in terms of granule fluidity, tablet friability, hardness, and tablet weight difference.

[0078] Example 3

[0079] The prescription of the tranexamic acid pharmaceutical composition of the present embodiment is as follows:

[0080]

[0081]

[0082] The preparation process is the same as the fluidized bed granulation process in Example 2.

[0083] Test Example 5

[0084] The tranexamic acid composition tablets of the above prescriptions 15-21 were subjected to quality testing, and the results are shown in the following table:

[0085]

[0086] The stickiness and astringency during tableting are shown in the following table:

[0087] Tablet Compression Prescription 15 No stickiness or astringency Prescription 16 No stickiness or astringency Prescription 17 No stickiness, slight astringency; cracking when pressing high hardness Prescription 18 No stickiness or astringency Prescription 19 No sticking or astringency; cracking occurs when pressing high hardness Prescription 20 No stickiness or astringency Prescription 21 Unable to compress tablets continuously, with astringent effect

[0088] From the above results, it can be seen that: compared with prescription 17, prescriptions 11, 15 and 16 have a long disintegration time for the composition tablets prepared when the proportion of hydrogenated castor oil is 2-4 parts, while the disintegration time of the composition tablets prepared when the proportion of hydrogenated castor oil is 1 part is shorter; compared with prescriptions 19 and 21, prescriptions 12, 18 and prescription 20 have a larger difference in tablet weight when colloidal silicon dioxide is not included, and there is a phenomenon of cracking when high hardness is pressed; when the proportion of colloidal silicon dioxide is 6 parts, the composition has a sticky phenomenon when tableting, and cannot be pressed continuously, and the disintegration time is shortened; compared with no addition of colloidal silicon dioxide, the composition tablets with a proportion of colloidal silicon dioxide of 2-5 parts have better friability, hardness and tablet weight differences.

[0089] Test Example 6

[0090] The dissolution curves of the tranexamic acid composition tablets of the above prescriptions 11, 12 and 15-21 and the reference preparation in a pH 1.2 medium were tested, and the results are shown in the following table:

[0091]

[0092] From the above table, it can be seen that the dissolution data of prescriptions 11, 15, 16 and 17 show that the composition tablets prepared when the proportion of hydrogenated castor oil is 2-4 parts are more similar to the reference preparation, and when the proportion of hydrogenated castor oil is 1 part, the active ingredient of the prepared composition tablets is also dissolved and released faster; compared with prescriptions 12, 18, 19, 20 and 21, the composition tablets prepared when the proportion of colloidal silicon dioxide is 2-5 parts are more similar to the reference preparation, and when no colloidal silicon dioxide is added or the proportion of colloidal silicon dioxide is too much (such as 6 parts in prescription 21), the active ingredient of the prepared composition tablets is also dissolved and released faster.

[0093] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A tranexamic acid pharmaceutical composition, characterized in that, The invention is composed of the following raw materials and auxiliary materials in parts by weight: 100-120 parts of tranexamic acid, 5-8 parts of povidone, 3-7 parts of calcium hydrogen phosphate dihydrate, 2-4 parts of cross-linked sodium carboxymethyl cellulose, 2-5 parts of colloidal silicon dioxide, 1-3 parts of magnesium stearate and 2-4 parts of oil-based lubricating auxiliary materials; The oil-based lubricating auxiliary material is selected from at least one of glyceryl distearate, glyceryl behenate and hydrogenated castor oil.

2. The tranexamic acid pharmaceutical composition according to claim 1, characterized in that The preparation is composed of the following raw and auxiliary materials in parts by weight: 100 parts of tranexamic acid, 5 parts of povidone, 6 parts of calcium hydrogen phosphate dihydrate, 3 parts of cross-linked sodium carboxymethyl cellulose, 2 parts of colloidal silicon dioxide, 1 part of magnesium stearate and 3 parts of oil-based lubricating auxiliary materials.

3. The tranexamic acid pharmaceutical composition according to claim 1, characterized in that The grease-based lubricating auxiliary material is hydrogenated castor oil.

4. The tranexamic acid pharmaceutical composition according to any one of claims 1 to 3, characterized in that The tranexamic acid pharmaceutical composition is prepared by a fluidized bed granulation process.

5. The preparation process of the tranexamic acid pharmaceutical composition according to any one of claims 1 to 3, characterized in that: The following steps are involved: (1) Preheating: Add tranexamic acid and calcium hydrogen phosphate dihydrate into a fluidized bed granulator, mix well, and preheat; (2) dissolving povidone in water to obtain a povidone solution; (3) spraying a povidone solution and drying to obtain dry granules; (4) adding cross-linked sodium carboxymethyl cellulose and colloidal silicon dioxide to the dry granules and mixing evenly, and then adding magnesium stearate and a lubricating auxiliary material such as oil and fat and mixing evenly to obtain a total mixed granule; (5) The total mixed granules are compressed into tablets.

6. The preparation process according to claim 5, characterized in that: In step (1), the preheating temperature is 50±5°C.

7. The preparation process according to claim 5, characterized in that: In step (2), the mass concentration of the povidone solution is 2-10%.

8. The preparation process according to claim 5, characterized in that: In step (3), the injection rate is 7-15 mL / min, the material temperature is 25-35°C; the drying temperature is 60°C, and the drying end point LOD is <1.0%.

9. The preparation process according to claim 5, characterized in that: In step (5), the tableting standards are: disintegration time > 10 min, tablet weight difference ≤ 5%, friability ≤ 0.8% and hardness value 50-70N.

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