Preparation method of ursodesoxycholic acid capsule

Abstract

The invention discloses a preparation method of ursodesoxycholic acid capsules. The preparation method comprises the following steps: (1) preparing materials; (2) preparing ursodesoxycholic acid nanocrystals; (3) wet granulation; (4) drying; and (5) total mixing and capsule filling. The ursodesoxycholic acid raw material is pretreated by adopting a nanocrystalline preparation technology (a wet medium grinding method), so that ursodesoxycholic acid particles can still have relatively good fluidity and dissolution rate under the condition of relatively large particle size, the metal adhesion is relatively weak, and the material loss can be reduced; according to the ursodesoxycholic acid capsule, ursodesoxycholic acid is taken as a raw material, lauryl sodium sulfate and povidone K30 are taken as stabilizers, the ursodesoxycholic acid capsule is prepared through wet granulation, drying, total mixing and capsule filling, and the process is simple in step and suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of ursodeoxycholic acid, in particular to a preparation method of ursodeoxycholic acid capsules. Background Art

[0002] Ursodeoxycholic acid (3a,7β-dihydroxy-5β-cholanoic acid) is a dihydroxycholic acid, the main active ingredient in bear bile. It promotes the hydrolysis of fats and fatty acids and is clinically used to treat various gallstone diseases and acute and chronic liver diseases. Ursodeoxycholic acid also has beneficial effects on primary bile acid cirrhosis, primary sclerosing cholangitis, and chronic active hepatitis.

[0003] Ursodeoxycholic acid is a poorly soluble drug, often resulting in low solubility and ultimately low bioavailability. Traditional ursodeoxycholic acid formulations use micronized raw materials (such as CN109568288A) to improve solubility. However, micronization does not guarantee good solubility, primarily because micronization easily forms a hydrophobic protective layer. Furthermore, smaller particles increase the specific surface area and molecular and electrostatic attraction, leading to decreased fluidity and strong agglomeration and metal adhesion. Furthermore, to ensure dissolution, extremely small particles must be prepared after granulation, resulting in significant material loss in large-scale industrial production. Summary of the Invention

[0004] The invention aims to solve the problem of serious material loss of ursodeoxycholic acid in the prior art and provides a preparation method of ursodeoxycholic acid capsules which can reduce material loss while ensuring dissolution.

[0005] In order to achieve the above object, the present invention adopts the following technical solution: a method for preparing ursodeoxycholic acid capsules of the present invention comprises the following steps: (1) Ingredients: Weigh 30-29 kg of ursodeoxycholic acid, 1.875-2.625 kg of sodium lauryl sulfate, 5.625-7.5 kg of povidone K30, 0.4-0.6 kg of colloidal silicon dioxide, 6-7.5 kg of corn starch, and 0.1-0.2 kg of magnesium stearate, and set aside. In the present invention, sodium lauryl sulfate and povidone K30 are stabilizers, and magnesium stearate is a lubricant.

[0006] (2) Preparation of ursodeoxycholic acid nanocrystals: Ursodeoxycholic acid, sodium lauryl sulfate, povidone K30, and an appropriate amount of water are mixed, ground, and freeze-dried to obtain ursodeoxycholic acid nanocrystals with a D90 of no greater than 300 nm and a D99 of no greater than 450 nm. The amount of water added is preferably such that the mass percentage of ursodeoxycholic acid is 70-80%.

[0007] (3) Wet granulation: Dissolve corn starch (11-12% by weight) in water to obtain a wetting agent; mix ursodeoxycholic acid nanocrystals, colloidal silicon dioxide, and the remaining corn starch to obtain a premix; add the wetting agent to the premix and perform wet stirring granulation to obtain wet granules.

[0008] (4) Drying: The wet granules are dried in a fluidized bed to obtain ursodeoxycholic acid granules.

[0009] (5) Total mixing and capsule filling: Mix the magnesium stearate and ursodeoxycholic acid granules evenly and fill the capsules according to the product specifications.

[0010] Preferably, in step (2), the grinding medium has a diameter of 0.5 mm and the grinding time is 85 min.

[0011] Preferably, in step (3), the mass percentage of corn starch in the wetting agent is 11-12%.

[0012] Preferably, in step (3), the stirring speed of the wet stirring granulation is 1000 rpm.

[0013] Preferably, in step (3), the particle size of the wet granules is 40-60 mesh.

[0014] Preferably, in step (4), the inlet air temperature of the fluidized bed drying is 45°C-50°C, and the material is dried to a moisture content of <3.0%.

[0015] Therefore, the present invention has the following beneficial effects: (1) The ursodeoxycholic acid raw material is pretreated using nanocrystal preparation technology (wet media grinding method), so that the ursodeoxycholic acid particles can still have good fluidity and solubility at a larger particle size, and have weak metal adhesion, which can reduce material loss; (2) Using sodium lauryl sulfate and povidone K30 as stabilizers, ursodeoxycholic acid capsules were prepared by wet granulation, drying, mixing, and capsule filling. The process steps are simple and suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 This is a comparison diagram of observations of a glass bottle containing ursodeoxycholic acid granules in Example 1 and a glass bottle containing ursodeoxycholic acid granules in Comparative Example 1.

[0017] Figure 2 This is a comparison of observations after pouring out the materials from the glass bottle containing the ursodeoxycholic acid granules in Example 1 and the glass bottle containing the ursodeoxycholic acid granules in Comparative Example 1. DETAILED DESCRIPTION

[0018] The present invention will be further described below with reference to the accompanying drawings and specific embodiments.

[0019] Example 1 (1) Ingredients: Weigh the raw materials according to the mass of 30 kg ursodeoxycholic acid, 1.875 kg sodium lauryl sulfate, 5.625 kg povidone K30, 0.4 kg colloidal silicon dioxide, 6 kg corn starch, and 0.1 kg magnesium stearate and set aside.

[0020] (2) Preparation of ursodeoxycholic acid nanocrystals: ursodeoxycholic acid, sodium lauryl sulfate, povidone K30 and an appropriate amount of water (the amount of water added is based on the ursodeoxycholic acid mass percentage of 70%) are mixed and ground. The grinding medium diameter is 0.5 mm and the grinding time is 85 min. The mixture is freeze-dried in a freeze dryer to obtain ursodeoxycholic acid nanocrystals with a D90 of no more than 300 nm and a D99 of no more than 450 nm.

[0021] (3) Wet granulation: Dissolve corn starch (11% by weight of the total corn starch) in water to obtain a wetting agent; mix ursodeoxycholic acid nanocrystals, colloidal silicon dioxide, and the remaining corn starch to obtain a premix; add the wetting agent to the premix and perform wet stirring granulation to obtain wet granules with a particle size of 40 mesh.

[0022] (4) Drying: The wet granules are dried in a fluidized bed at an air inlet temperature of 45°C until the moisture content of the material is less than 3.0%, thereby obtaining ursodeoxycholic acid granules.

[0023] (5) Total mixing and capsule filling: After the magnesium stearate and ursodeoxycholic acid granules are mixed evenly, capsules are filled using a capsule filling machine according to the product specifications.

[0024] Comparative Example 1 The difference between Comparative Example 1 and Example 1 is that step (2) is replaced by the following method: micronized ursodeoxycholic acid is used, and the micronized ursodeoxycholic acid is mixed with sodium lauryl sulfate and povidone K30 to replace ursodeoxycholic acid nanocrystals. The remaining steps are the same as in Example 1.

[0025] Comparative Example 2 The difference between Comparative Example 2 and Example 1 is that in step (3), wet granules with a particle size of 80 mesh are obtained, and the remaining steps are the same as in Example 1.

[0026] (1) Metal adhesion comparison test The metal adhesion of the ursodeoxycholic acid granules in Example 1 and the ursodeoxycholic acid granules in Comparative Example 1 was compared. The specific comparison method was as follows: the ursodeoxycholic acid granules in Example 1 and the ursodeoxycholic acid granules in Comparative Example 1 were respectively placed in the same glass bottle (such as Figure 1 Then pour out the ursodeoxycholic acid granules in the bottle and observe the adhesion of the ursodeoxycholic acid granules to the wall (as shown in the figure). Figure 2 shown).

[0027] from Figure 2 It can be seen that the amount of ursodeoxycholic acid particles adhered to the glass bottle in Example 1 is relatively small, indicating that the ursodeoxycholic acid particles of the present invention have weak metal adhesion.

[0028] (2) Fluidity test The flowability of drug powders or granules is a critical physical property in the preparation of solid dosage forms. This applies to every process, from raw material mixing and excipient mixing to boiling granulation, packaging, and tableting. Especially during tableting, excellent granule flowability is crucial to ensure that granules flow freely and continuously into the die, ensuring uniform filling, minimizing friction and adhesion to the die wall during tableting, and reducing tablet weight variability.

[0029] The specific method of the fluidity test is: 1. Use the BT-1000 powder comprehensive characteristics tester to measure the angle of repose: the acute angle between the inclined surface of the powder accumulation and the horizontal surface at the bottom in a static equilibrium state.

[0030] 2. Use the BT-1000 Powder Comprehensive Property Tester to measure the bulk density and tap density and calculate the Carr Index. Tap density is calculated by filling a specific container with a certain weight (or volume) of powder and vibrating the container with a certain intensity to break up the gaps between the powder particles and compact the particles. The volume and mass at this point are then measured to calculate the density. Bulk density is calculated by measuring the volume and mass of the powder after it is naturally filled in the container. Carr Index = (Tap Density - Bulk Density) / Tap Density × 100%.

[0031] The measurement results of the angle of repose and Carr's index are shown in Table 1.

[0032] Table 1 Measurement results of angle of repose and Carr index As can be seen from Table 1, the angles of repose and Carr's indexes of Example 1 and Comparative Example 2 are close to each other and better than Comparative Example 1, indicating that the ursodeoxycholic acid particles prepared from ursodeoxycholic acid nanocrystals in the present invention have very good fluidity, and the particle size has no significant effect on the fluidity of the ursodeoxycholic acid particles. Larger particles can be prepared to reduce material loss.

[0033] (III) Dissolution test Test method: Follow the second method of dissolution method, paddle method, conditions: medium pH 7.5 phosphate buffer, 900 mL, paddle method + sinker, rotation speed: 75 rpm. Test results are shown in Table 2: Table 2 Dissolution test results As can be seen from Table 2, the dissolution rates of Example 1 and Comparative Example 2 are good and the difference is small, and the particle size requirement is low. This shows that even large particles of 40-60 mesh made of ursodeoxycholic acid nanocrystals can still ensure good dissolution rates, so larger particles can be made to reduce material loss.

[0034] The embodiment described above is only a preferred solution of the present invention and does not limit the present invention in any form. Other variations and modifications are possible without exceeding the technical solution described in the claims.

Claims

1. A method for preparing ursodeoxycholic acid capsules, characterized in that: The following steps are involved: (1) Ingredients: Weigh the raw materials according to the mass of 30-29 kg ursodeoxycholic acid, 1.875-2.625 kg sodium lauryl sulfate, 5.625-7.5 kg povidone K30, 0.4-0.6 kg colloidal silicon dioxide, 6-7.5 kg corn starch, and 0.1-0.2 kg magnesium stearate and set aside; (2) Preparation of ursodeoxycholic acid nanocrystals: ursodeoxycholic acid, sodium lauryl sulfate, povidone K30 and an appropriate amount of water are mixed, ground, and freeze-dried to obtain ursodeoxycholic acid nanocrystals with a D90 of no more than 300 nm and a D99 of no more than 450 nm; (3) Wet granulation: Dissolve corn starch (11-12% by weight) in water to obtain a wetting agent; mix ursodeoxycholic acid nanocrystals, colloidal silicon dioxide, and the remaining corn starch to obtain a premix; add the wetting agent to the premix and perform wet stirring granulation to obtain wet granules; (4) Drying: The wet granules are subjected to fluidized bed drying to obtain ursodeoxycholic acid granules; (5) Total mixing and capsule filling: Mix the magnesium stearate and ursodeoxycholic acid granules evenly and fill the capsules according to the product specifications.

2. The method for preparing ursodeoxycholic acid capsules according to claim 1, wherein: In step (2), the grinding medium diameter is 0.5 mm and the grinding time is 85 min.

3. The method for preparing ursodeoxycholic acid capsules according to claim 1, wherein: In step (3), the mass percentage of corn starch in the wetting agent is 11-12%.

4. The method for preparing ursodeoxycholic acid capsules according to claim 1, wherein: In step (3), the stirring speed of the wet stirring granulation is 1000 rpm.

5. The method for preparing ursodeoxycholic acid capsules according to claim 1, wherein: In step (3), the particle size of the wet granules is 40-60 mesh.

6. The method for preparing ursodeoxycholic acid capsules according to claim 1, characterized in that: In step (4), the inlet air temperature of the fluidized bed drying is 45°C-50°C, and the material is dried to a moisture content of <3.0%.

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