Pancreatic kininogenase tablet and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, and particularly discloses a pancreatic kallidinogenase tablet and a preparation method thereof.The preparation method comprises the steps that firstly, a pancreatic kallidinogenase raw material medicine is smashed at low temperature, the temperature is controlled to be smaller than or equal to 10 DEG C, liquid nitrogen assists in ensuring enzyme activity, and fine enzyme powder is obtained after smashing and sieving; when the ingredients are mixed, the ingredients are prepared according to specific parts by weight, and are sequentially and regularly stirred under the protection of inert gas to ensure that the ingredients are uniform. Taking purified water as a wetting agent for wet granulation, and accurately controlling spraying parameters and the rotating speed of a granulator to obtain wet granules with proper particle sizes; fluidized bed drying is performed, temperature and wind speed are precisely controlled, and the particle water content reaches the standard. A punch and a die are optimized during tabletting, a double-layer coating process is built inside and outside, and the environment is strictly controlled during curing and subpackaging. According to the method, the quality of the tablets is comprehensively improved, the enzyme activity preservation rate is high, components are uniform, forming is good, stability is high, dissolution is good, bioavailability is excellent, high-quality selection is provided for clinical medication, and the method has great application and popularization value.

Description

Technical Field

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

[0002] As a vasodilator, pancreatic kallikrein has important applications in the medical field. It has the function of improving microcirculation and is mainly used to treat microcirculatory disorders, such as diabetic nephropathy, peripheral neuropathy, retinopathy, fundus disease and ischemic cerebrovascular disease. It can also assist in the treatment of hypertension. For example, in the treatment of diabetic nephropathy, pancreatic kallikrein can play a positive role in delaying the progression of the disease by improving the microcirculation of the kidneys.

[0003] At present, kallikrein can be prepared into various preparation forms for clinical use according to conventional preparation methods, among which tablets are one of the common dosage forms. However, in the prior art, there are some problems in the preparation of kallikrein tablets.

[0004] From the technical content disclosed in patent CN200710110454.4 (publication number: CN101069742A, authorization announcement number: CN101069742B), although the invention proposes to add sodium carboxymethyl starch as a disintegrant to the core of the kallikreinogenase tablet to improve the tablet quality, this conventional preparation method still has limitations in practical applications. For example, it only focuses on the use of disintegrants, and the pretreatment method for kallikreinogenase raw materials is relatively simple, and fails to fully consider that kallikreinogenase is an enzyme, and its activity may be affected by various factors such as temperature and humidity during the preparation process. In the process of mixing raw materials, there is no mention of strict control of environmental conditions, which may lead to uneven mixing and affect the quality stability of tablets.

[0005] Another example is a pancreatic kallikrein enteric-coated tablet and its preparation method disclosed in patent CN202311467994.3 (application publication number: CN117180215A, authorization announcement number: CN117180215B). This method prepares enteric-coated tablets through specific spray solution preparation and one-step granulation and other steps. Although it improves the potency and quality of the product to a certain extent, the control of process parameters in wet granulation, drying and coating is not fine enough. For example, during wet granulation, the spraying method, dosage of the wetting agent and the parameter setting of the granulation equipment are not accurate enough, which may lead to uneven particle size distribution of the particles, thereby affecting the molding and dissolution performance of the tablets. During the coating process, the selection of coating materials and the control of the coating process are also relatively conventional, and cannot meet the needs of improving tablet stability and bioavailability.

[0006] In summary, the existing preparation methods of kallikrein tablets have certain deficiencies in raw material processing, mixing process, granulation process, drying process, tableting process, coating process, and curing and packaging of finished products, resulting in room for improvement in quality stability, activity retention, dissolution performance, and bioavailability of the prepared kallikrein tablets. Therefore, it is necessary to develop a new preparation method to solve the above problems and improve the quality and efficacy of kallikrein tablets. Summary of the invention

[0007] 1. Technical issues to be solved

[0008] In view of the deficiencies of the prior art, the present invention provides a kallikreinogenase tablet and a preparation method thereof, which solve the problems raised in the above-mentioned background technology.

[0009] (II) Technical solution

[0010] In order to achieve the above object, the present invention discloses a method for preparing a pancreatic lipase inhibitor, comprising the following steps:

[0011] Step 1, raw material pretreatment: take pancreatic kallikreinogenase raw material and perform low-temperature pulverization treatment, control the pulverization temperature ≤10°C, and pass through a 100-mesh sieve after pulverization to obtain enzyme powder with a particle size of ≤150μm;

[0012] Step 2, mixing ingredients: prepare the following raw materials by weight: 10-20 parts of kallikrein powder, 40-50 parts of microcrystalline cellulose, 15-25 parts of hypromellose, 5-10 parts of lactose, 2-5 parts of nano-silicon dioxide, and 1-3 parts of magnesium stearate; premix the kallikrein powder with lactose, add microcrystalline cellulose and hypromellose, and stir for 20 minutes under the protection of inert gas at a stirring speed of 30-50 r / min; then add nano-silicon dioxide and continue stirring for 10 minutes, and finally add magnesium stearate and mix for 5 minutes;

[0013] Step 3, wet granulation: the mixture is evenly sprayed with purified water as a wetting agent using a high-pressure atomizing spray gun, the amount of the wetting agent is 15%-20% of the total weight of the mixture, and the spray pressure is controlled at 0.3-0.5MPa; after wetting, it is transferred to a wet granulator and granulated at a shear speed of 200-300r / min for 10 minutes to obtain wet granules with a particle size range of 0.5-1.2mm;

[0014] Step 4: Fluidized bed drying: Place the wet granules in a fluidized bed dryer and set the air inlet temperature to 35-40°C and the wind speed to 1.5-2.0 m / s. 3 / s, dried to a granular moisture content of ≤3%;

[0015] Step 5, tableting: Add the dried granules into a rotary tablet press, set the tableting pressure to 5-10 kN, the mold diameter to 8-12 mm, and press to obtain a tablet core;

[0016] Step 6: Coating: a double-layer coating process is used, the inner layer is a hydroxypropyl cellulose coating solution, and the outer layer is a polyvinyl alcohol-polyethylene glycol composite film coating solution, and the coating weight gain is 1%-2% and 3%-5% of the tablet core weight respectively;

[0017] Step 7. Curing and packaging: Place the coated tablets in a light-proof environment, control the temperature at 20-25°C and the humidity at 30%-40%, let them stand and cure for 48 hours, and seal them after packaging.

[0018] Preferably, the low-temperature pulverization treatment in step 1 adopts a liquid nitrogen-assisted low-temperature pulverizer, the pulverizer cavity temperature is maintained at 5-8° C., and the pulverization time is 5-8 minutes.

[0019] Preferably, the inert gas in step 2 is nitrogen or argon, and the gas purity is ≥99.99%. During the mixing process, the gas is continuously introduced and the gas pressure is maintained at 0.1-0.2 MPa.

[0020] Preferably, in the step 3, the ratio of the speed of the stirring blade to the cutting blade of the wet granulator is 2:1, and the speed of the cutting blade is 100-150 r / min.

[0021] Preferably, in step 5, the punch surface of the rotary tablet press is coated with a polytetrafluoroethylene coating, and the die gap is controlled at 0.05-0.1 mm.

[0022] Preferably, the double-layer coating process in step six is ​​as follows: the inner coating liquid contains 5%-8% (w / v) hydroxypropyl cellulose, the outer coating liquid contains 3%-5% (w / v) polyvinyl alcohol and 1%-3% (w / v) polyethylene glycol, and the atomized particle size of the coating liquid is 20-50 μm.

[0023] Preferably, the curing environment in step seven adopts a temperature and humidity linkage control system, with temperature fluctuation ≤±1°C and humidity fluctuation ≤±5%.

[0024] Another object of the present invention is to provide a kallikrein tablet, which comprises 10-20 parts of kallikrein powder, 40-50 parts of microcrystalline cellulose, 15-25 parts of hypromellose, 5-10 parts of lactose, 2-5 parts of nano silicon dioxide, and 1-3 parts of magnesium stearate; the tablet surface is a double-layer coating structure, the inner coating thickness is 10-20 μm, the outer coating thickness is 30-50 μm, the tablet hardness is 50-80N, and the disintegration time is ≤15 minutes.

[0025] (III) Beneficial technical effects

[0026] First, in the raw material pretreatment stage, the pulverization temperature is strictly limited to ≤10°C, and the cavity temperature is accurately maintained at 5-8°C with the help of liquid nitrogen-assisted low-temperature pulverizer. After 5-8 minutes of pulverization operation, the biological activity of pancreatic kallikreinogenase is greatly guaranteed. Compared with conventional pulverization methods, the loss of enzyme activity is significantly reduced. Experimental verification shows that the enzyme activity preservation rate can be increased by about 30%. The enzyme powder with a particle size of ≤150μm obtained by such fine treatment not only creates a good start for the subsequent mixing of ingredients, but also ensures the efficiency and sufficiency of the raw material reaction in the entire preparation process.

[0027] Secondly, the innovative measures in the ingredient mixing stage have achieved remarkable results. After preparing the raw materials in a specific proportion, high-purity (≥99.99%) nitrogen or argon is introduced as an inert gas for protection, and it is continuously introduced throughout the mixing process to stably maintain the air pressure at 0.1-0.2MPa. This effectively avoids the risk of oxidative inactivation of kallikrein during the mixing process and consolidates the active foundation of the enzyme. At the same time, stirring is carried out according to strict sequence and time requirements. First, kallikrein powder is premixed with lactose and then blended into microcrystalline cellulose and hydroxypropyl methylcellulose. It is stirred at a speed of 30-50r / min for 20 minutes, and then nano-silicon dioxide is added and stirred for 10 minutes. Finally, magnesium stearate is mixed and stirred for 5 minutes. Such an orderly operation promotes the uniform interweaving of various components, completely eliminates the disadvantages of material agglomeration, and effectively guarantees the precise consistency of the content of drug ingredients in each tablet, greatly improving the stability and reliability of product quality.

[0028] Third, the wet granulation process stands out with its precise process parameters. Purified water is selected as the wetting agent, and it is evenly sprayed with a high-pressure atomizing spray gun. The amount of wetting agent is precisely controlled at 15%-20% of the total weight of the mixture, and the spray pressure is stabilized at 0.3-0.5MPa. At the same time, the wet granulator uses a specific stirring paddle and cutting knife speed ratio (2:1, cutting knife speed is 100-150r / min) to continue granulation for 10 minutes. In this way, the prepared wet granules have a particle size range of precisely controlled at 0.5-1.2mm and have ideal sphericity and compactness. This not only paves the way for the subsequent drying process, but also makes it easy to achieve excellent quality tablets with moderate hardness and small tablet weight differences in the tablet pressing stage.

[0029] Fourthly, fine temperature control and wind speed regulation in the fluidized bed drying process are crucial. Set the air inlet temperature to 35-40℃ and the wind speed to 1.5-2.0m 3 / s, until the moisture content of the granules is accurately dried to ≤3%. Such precise condition setting not only cleverly avoids the damage of high temperature to the activity of pancreatic kallikreinogenase, but also drives away moisture quickly with high efficiency, so that the dried granules have excellent fluidity and no adhesion problems, providing high-quality materials for the tableting process, and effectively reducing quality defects such as tablet cracking and loose tablets derived from improper drying.

[0030] Fifth, during the tableting stage, the punch surface of the rotary tablet press is carefully coated with polytetrafluoroethylene, the mold gap is precisely controlled at 0.05-0.1mm, and the tableting pressure is reasonably set at 5-10kN, and the mold diameter is 8-12mm. The coated punch greatly reduces the probability of material sticking to the punch, the precise control of the mold gap ensures that the tablet thickness is uniform, and the scientific setting of the tableting pressure helps the tablet hardness meet the standard.

[0031] Sixth, the double-layer coating process builds a solid protective barrier. The inner layer uses hydroxypropyl cellulose coating liquid, and the outer layer uses polyvinyl alcohol-polyethylene glycol composite film coating liquid. The coating weight gain is precisely set to 1%-2% and 3%-5% of the tablet core weight, respectively. The inner layer coating liquid contains 5%-8% (w / v) hydroxypropyl cellulose, and the outer layer coating liquid contains 3%-5% (w / v) polyvinyl alcohol and 1%-3% (w / v) polyethylene glycol. The atomized particle size of the coating liquid is finely controlled at 20-50μm. This unique double-layer coating structure, on the one hand, builds a strong protective line for the inner layer of pancreatic kallikreinogenase, effectively blocking the invasion of adverse factors such as external moisture and oxygen, and effectively maintaining the activity of the enzyme; on the other hand, the outer layer of composite film coating liquid gives the tablets excellent moisture and wear resistance, significantly improves the storage stability of the tablets, and greatly extends the shelf life. DETAILED DESCRIPTION

[0032] In order to facilitate the understanding of the present invention, the present invention will be described more fully below. Preferred embodiments of the present invention are given below. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive.

[0033] Example 1

[0034] Step 1: Place the pancreatic kallikreinogenase API in a liquid nitrogen-assisted low-temperature pulverizer, control the chamber temperature at 6°C, and pulverize for 7 minutes. After pulverization, pass through a 100-mesh sieve to obtain enzyme powder with a particle size of ≤140 μm.

[0035] Step 2: Weigh 15 parts of pancreatic kallikreinogenase powder, 45 parts of microcrystalline cellulose, 20 parts of hypromellose, 8 parts of lactose, 3 parts of nano-silicon dioxide, and 2 parts of magnesium stearate. Premix the enzyme powder with lactose, add microcrystalline cellulose and hypromellose, and stir at 40r / min for 20 minutes under nitrogen protection (purity 99.99%, air pressure 0.15MPa). Add nano-silicon dioxide and continue stirring for 10 minutes, and finally add magnesium stearate and mix for 5 minutes.

[0036] Step 3: Transfer the mixture to a wet granulator and evenly wet it with purified water (18%) through a high-pressure atomizing spray gun (pressure 0.4 MPa). Control the stirring blade speed to 250 r / min and the cutting blade speed to 125 r / min, granulate for 10 minutes, and obtain 0.8-1.0 mm wet granules.

[0037] Step 4: Place the wet granules in a fluidized bed dryer and set the air inlet temperature to 38°C and the wind speed to 1.8 m / s. 3 / s, dried to a moisture content of 2.5%.

[0038] Step 5: Add the dried granules into a rotary tablet press coated with polytetrafluoroethylene, set the tableting pressure to 8 kN, the mold diameter to 10 mm, and press the tablet cores.

[0039] Step 6: A double-layer coating process is used, with the inner layer being a 6% hydroxypropyl cellulose solution (coating weight gain 1.5%), and the outer layer being a 4% polyvinyl alcohol and 2% polyethylene glycol composite solution (coating weight gain 4%), and the atomized particle size is 30 μm.

[0040] Step 7: Place the coated tablets in a temperature and humidity linkage control box (24°C ± 1°C, 35% ± 5% humidity) away from light for curing for 48 hours, and then package and seal.

[0041] Example 2

[0042] Step 1: The crushing temperature is controlled at 8°C and the crushing time is 6 minutes to obtain enzyme powder with a particle size of ≤130μm. Step 2: The raw material ratio is 18 parts of pancreatic kallikreinogenase powder, 48 parts of microcrystalline cellulose, 22 parts of hypromellose, 6 parts of lactose, 4 parts of nano silicon dioxide, and 2.5 parts of magnesium stearate. The mixing process is protected by argon gas (air pressure 0.12MPa).

[0043] Step 3: The wetting agent dosage is 17%, the spray pressure is 0.35 MPa, and the speed ratio of the stirring blade to the cutting blade is 2:1 (280 r / min: 140 r / min).

[0044] Step 6: The concentration of the inner coating solution is 7%, and the outer coating solution contains 3.5% polyvinyl alcohol and 1.8% polyethylene glycol. The remaining steps are the same as in Example 1.

[0045] Example 3

[0046] Step 5: Adjust the tableting die diameter to 9 mm and the tableting pressure to 10 kN.

[0047] Step 6: The inner coating weight is increased by 2%, the outer coating weight is increased by 3.5%, and the atomized particle size is 40 μm. The other parameters are the same as those in Example 1.

[0048] Comparative Example 1

[0049] Step 1: No low-temperature grinding was performed, but the product was ground at room temperature (25°C) and passed through an 80-mesh sieve to obtain enzyme powder with a particle size of 180 μm.

[0050] Step 2: directly exposing to air and mixing without using inert gas protection. The remaining steps are the same as in Example 1.

[0051] Comparative Example 2

[0052] Step 3: The wetting agent dosage is 25%, and the granulation shear speed is increased to 400r / min.

[0053] Step 6: Use a single layer coating (hydroxypropyl cellulose solution only, weight gain 5%). The remaining steps are the same as in Example 1.

[0054] Comparative Example 3

[0055] Step 4: Fluidized bed drying temperature increased to 50°C, wind speed 3m 3 / s, moisture content after drying is 1.8%. Step 7: The humidity of the curing environment is not controlled (ambient humidity is 60%). The remaining steps are the same as in Example 1. Performance test data:

[0056] Table 1 Comparison of key parameters between the examples and the comparative examples

[0057]

[0058] Table 2 Product quality test results

[0059]

[0060] Example 4

[0061] Step 1: Use liquid nitrogen-assisted low-temperature pulverizer, with a chamber temperature of 5°C and a pulverization time of 8 minutes, and sieve through a 100-mesh sieve to obtain enzyme powder with a particle size of ≤145μm.

[0062] Step 2: The raw material ratio is 12 parts of pancreatic kallikrein powder, 50 parts of microcrystalline cellulose, 18 parts of hypromellose, 7 parts of lactose, 2.5 parts of nano silicon dioxide, and 1.5 parts of magnesium stearate. The mixing process is stirred at 35 r / min for 20 minutes under argon protection (gas pressure 0.18 MPa).

[0063] Step 3: The dosage of wetting agent is 16%, the spray pressure is 0.45 MPa, the stirring blade speed is 220 r / min, the cutting knife speed is 110 r / min, and 0.6-1.1 mm wet particles are obtained.

[0064] Step 4: Fluidized bed drying air inlet temperature 36°C, wind speed 1.6m 3 / s, moisture content after drying is 2.8%.

[0065] Step 5: The tableting die diameter is 11 mm, the pressure is 7 kN, and the punch coating thickness is increased to 0.1 mm.

[0066] Step 6: The concentration of the inner coating solution is 5% (weight gain 1.2%), the outer layer contains 5% polyvinyl alcohol and 1.5% polyethylene glycol (weight gain 3.8%), and the atomized particle size is 25 μm.

[0067] Step 7: The curing environment is controlled at 22°C ± 1°C and humidity is 38% ± 5%. The rest is the same as in Example 1.

[0068] Example 5

[0069] Step 2: The raw material ratio is adjusted to 20 parts of kallikreinogenase powder, 40 parts of microcrystalline cellulose, 25 parts of hypromellose, 5 parts of lactose, 5 parts of nano silicon dioxide, and 3 parts of magnesium stearate. The mixing process is protected by nitrogen (air pressure 0.2 MPa) and the stirring speed is 50 r / min.

[0070] Step 3: Wetting agent dosage 20%, spray pressure 0.3 MPa, granulation shear speed 300 r / min, cutting knife speed 150 r / min.

[0071] Step 4: Drying temperature 40°C, wind speed 2.0m 3 / s, particle moisture content 2.3%.

[0072] Step 5: Tableting pressure is 10kN, mold diameter is 8mm, and tablet core thickness is adjusted to 3.5mm.

[0073] Step 6: The weight of the inner coating increases by 2%, the weight of the outer coating increases by 5%, and the atomized particle size is 50 μm.

[0074] Step 7: The curing time is extended to 60 hours, and the other parameters are the same as in Example 1.

[0075] Comparative Example 4

[0076] Step 2: Eliminate the lactose premixing step and directly mix all the excipients at once.

[0077] Step 3: The wetting agent dosage is 10% and the spray pressure is 0.6 MPa, resulting in particle adhesion.

[0078] Step 6: No polyethylene glycol is added to the outer coating solution, and only polyvinyl alcohol is used. The rest is the same as in Example 1.

[0079] Comparative Example 5

[0080] Step 4: Oven drying (static drying at 60°C for 4 hours) was used instead of fluidized bed drying, and the moisture content of the particles was reduced to 1.5%, but local coking occurred.

[0081] Step 5: The gap between the tablet pressing molds is expanded to 0.2 mm, and cracks appear on the edge of the tablet core. The rest is the same as in Example 1.

[0082] Table 3 Comparison of process parameters between Examples 4-5 and Comparative Examples 4-5

[0083]

[0084] Table 4 Extended performance test results

[0085]

[0086] Experimental data analysis:

[0087] Necessity of lactose premixing (Comparative Example 4): Failure to premix results in uneven mixing, tablet core hardness decreases by 42%, and friability increases by 275%, proving that the premixing step plays a key role in material dispersibility and tableting quality.

[0088] Advantages of fluidized bed drying (Comparative Example 5): Although oven drying can quickly dehydrate, the high temperature causes the enzyme activity loss rate to increase by 14.3% compared with Example 1, and the particle fluidity is poor (tablet crack rate>5%).

[0089] Coating synergistic effect: The single polyvinyl alcohol coating in Comparative Example 4 caused the tablets to absorb moisture and gain weight by 8% in the accelerated stability test, while the double-layer coating in Example 5 only absorbed moisture by 2.3%, indicating that the hydrophobic modification of PEG can significantly improve the moisture resistance.

[0090] Control of enzyme powder particle size: The enzyme activity retention rates of Examples 1-3 were 15.8-16.8 percentage points higher than that of Comparative Example 1, which verifies the protective effect of low-temperature pulverization on the enzyme molecular structure.

[0091] Example 6 (Optimization of limit parameters)

[0092] Step 1: The crushing temperature is reduced to 4°C (equipment limit), the crushing time is 10 minutes, and the enzyme powder particle size is ≤125μm.

[0093] Step 2: Use a high-precision loss-in-weight feeding system to control the mixing time error to ≤±5 seconds.

[0094] Step 5: The tableting pressure is increased to 12kN (the pressure limit of the mold), and the tablet density is increased to 1.25g / cm 3 .

[0095] Step 6: The outer coating atomization particle size was refined to 18μm, and the coating uniformity CV value was <3%. Result: The tablet dissolution T90 was shortened to 15 minutes, and the accelerated stability test showed that the 12-month activity retention rate was >94%.

[0096] The above examples further demonstrate that by precisely controlling the pulverization temperature, material mixing timing and coating atomization accuracy, the performance bottleneck of conventional processes can be overcome, and efficient and stable production of kallikreinogenase preparations can be achieved.

[0097] The above examples show that the use of low temperature grinding, inert gas protection, double coating and specific drying conditions can significantly improve the enzyme activity retention rate and product stability. The deviation of any process parameter in the comparative example leads to a decrease in key quality indicators, which verifies the necessity and synergistic effect of the process parameters of the present invention.

[0098] Although the embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that all equivalent changes and improvements made within the scope of the present invention should still fall within the scope of the patent coverage of the present invention.

Claims

1. A method for preparing a pancreatic kallikreinase tablet, characterized in that: The steps include: Step 1, raw material pretreatment: take pancreatic kallikreinogenase raw material and perform low-temperature pulverization treatment, control the pulverization temperature ≤10°C, and pass through a 100-mesh sieve after pulverization to obtain enzyme powder with a particle size of ≤150μm; Step 2, mixing ingredients: prepare the following raw materials by weight: 10-20 parts of kallikrein powder, 40-50 parts of microcrystalline cellulose, 15-25 parts of hypromellose, 5-10 parts of lactose, 2-5 parts of nano-silicon dioxide, and 1-3 parts of magnesium stearate; premix the kallikrein powder with lactose, add microcrystalline cellulose and hypromellose, and stir for 20 minutes under the protection of inert gas at a stirring speed of 30-50 r / min; then add nano-silicon dioxide and continue stirring for 10 minutes, and finally add magnesium stearate and mix for 5 minutes; Step 3, wet granulation: the mixture is evenly sprayed with purified water as a wetting agent using a high-pressure atomizing spray gun, the amount of the wetting agent is 15%-20% of the total weight of the mixture, and the spray pressure is controlled at 0.3-0.5MPa; after wetting, it is transferred to a wet granulator and granulated at a shear speed of 200-300r / min for 10 minutes to obtain wet granules with a particle size range of 0.5-1.2mm; Step 4: Fluidized bed drying: Place the wet granules in a fluidized bed dryer and set the air inlet temperature to 35-40°C and the wind speed to 1.5-2.0 m / s. 3 / s, dried to a granule moisture content of ≤3%; Step 5, tableting: Add the dried granules into a rotary tablet press, set the tableting pressure to 5-10 kN, the mold diameter to 8-12 mm, and press to obtain a tablet core; Step 6: Coating: a double-layer coating process is used, the inner layer is a hydroxypropyl cellulose coating solution, and the outer layer is a polyvinyl alcohol-polyethylene glycol composite film coating solution, and the coating weight gain is 1%-2% and 3%-5% of the tablet core weight respectively; Step 7. Curing and packaging: Place the coated tablets in a light-proof environment, control the temperature at 20-25°C and the humidity at 30%-40%, let them stand and cure for 48 hours, and seal them after packaging.

2. The method for preparing a pancreatic kallikreinase tablet according to claim 1, characterized in that: In the step 1, the low-temperature pulverization treatment is carried out using a liquid nitrogen-assisted low-temperature pulverizer, the pulverizer cavity temperature is maintained at 5-8° C., and the pulverization time is 5-8 minutes.

3. The method for preparing a pancreatic kallikreinase tablet according to claim 1, characterized in that: The inert gas in step 2 is nitrogen or argon with a gas purity of ≥99.99%. The gas is continuously introduced during the mixing process and the gas pressure is maintained at 0.1-0.2 MPa.

4. The method for preparing a pancreatic kallikreinase tablet according to claim 1, characterized in that: In the step 3, the ratio of the rotation speed of the stirring blade to the cutting blade of the wet granulator is 2:1, and the rotation speed of the cutting blade is 100-150 r / min.

5. The method for preparing a pancreatic kallikreinase tablet according to claim 1, characterized in that: In the step 5, the punch surface of the rotary tablet press is coated with a polytetrafluoroethylene coating, and the die gap is controlled at 0.05-0.1 mm.

6. The method for preparing a pancreatic kallikreinase tablet according to claim 1, characterized in that: The double-layer coating process in step six is ​​specifically as follows: the inner coating liquid contains 5%-8% (w / v) hydroxypropyl cellulose, the outer coating liquid contains 3%-5% (w / v) polyvinyl alcohol and 1%-3% (w / v) polyethylene glycol, and the atomized particle size of the coating liquid is 20-50 μm.

7. The method for preparing a pancreatic kallikreinase tablet according to claim 1, characterized in that: The curing environment in step seven adopts a temperature and humidity linkage control system, with temperature fluctuation ≤±1°C and humidity fluctuation ≤±5%.

8. A pancreatic kallikreinase tablet, characterized in that: Prepared by the method described in any one of claims 1 to 7, the composition includes 10-20 parts of kallikreinogenase powder, 40-50 parts of microcrystalline cellulose, 15-25 parts of hypromellose, 5-10 parts of lactose, 2-5 parts of nano silicon dioxide, and 1-3 parts of magnesium stearate; the tablet surface is a double-layer coating structure, the inner coating thickness is 10-20 μm, the outer coating thickness is 30-50 μm, the tablet hardness is 50-80N, and the disintegration time is ≤15 minutes.

Images