CN117838649A - Prednisolone enteric-coated sustained-release tablets and preparation method thereof - Google Patents

Abstract

The invention belongs to the technical field of medicine preparation, and in particular relates to a prednisone Long Chang sustained-release tablet and a preparation method thereof. The prednisone Long Chang soluble sustained-release tablet comprises a single-layer tablet core containing prednisolone and an enteric coating film, wherein the single-layer tablet core comprises the prednisolone, a sustained-release framework material, a release regulator and an adhesive; the enteric coating film is obtained by coating enteric coating liquid consisting of enteric coating materials, an anti-adhesion agent and a plasticizer on the surface of a single-layer tablet core, wherein other pharmaceutically acceptable additives can be included or not included in the components of the single-layer tablet core as required, the sustained-release tablet is taken once a day, the drug loading capacity is higher than that of a single dosage of a traditional dosage form drug, the effective blood concentration can be maintained for a long time, the condition of blood concentration fluctuation is greatly reduced, the stable and effective blood concentration can be obtained for a human body, and the treatment effect of the drug is ensured.

Description

Prednisolone enteric-coated sustained-release tablets and preparation method thereof

Technical Field

The invention belongs to the technical field of medicine preparation, and particularly relates to a prednisolone enteric-coated sustained-release tablet and a preparation method thereof.

Background technique

Prednisolone is a glucocorticoid with powerful anti-inflammatory, anti-allergic and immunosuppressive effects, and is widely used in the clinic to treat various inflammatory and immune diseases. However, the duration of prednisolone's efficacy in the body is short, and frequent administration is required, which not only brings inconvenience to patients, but also may increase the adverse reactions of the drug. Therefore, it is of great significance to develop an enteric-coated sustained-release tablet that can slowly release prednisolone.

The existing prednisolone sustained-release tablet Rayos is a delayed-release tablet made using SkyePharma's Geoclock patented technology. It does not release prednisone immediately after oral administration, but releases the drug about 4 hours later and reaches the peak blood concentration after 6 hours. This allows patients to take the drug before going to bed at 10 pm, and the drug is released until 2 am the next morning, reaching the peak blood concentration at 4 am. This preparation that takes the drug at night and releases the drug in the early morning is particularly suitable for treating joint stiffness caused by rheumatoid arthritis after waking up in the morning. Therefore, the main usage scenario of Rayos is to take the drug before going to bed. Multiple doses are required during the day, which often result in missed doses. Some patients even change the dosing regimen without authorization, thus failing to achieve the desired treatment purpose.

Hydroxypropyl methylcellulose, also known as hydroxypropyl methylcellulose (HPMC), is a polymer used as a pharmaceutical excipient to control the release of drugs from oral hydrophilic gel matrix tablets. The use of HPMC in hydrophilic gel matrix tablets has been widely approved by regulators. HPMC is easy to use and has a good safety record, which has been proven by a large number of studies. In view of this, it is of great significance to apply HPMC to the preparation of prednisolone enteric-coated sustained-release tablets to improve their sustained-release effect.

Summary of the invention

The present invention provides a prednisolone enteric-coated sustained-release tablet and a preparation method thereof. The sustained-release tablet can slowly release prednisolone, thereby prolonging the drug's action time, reducing the frequency of drug administration, improving patient compliance, and reducing adverse drug reactions.

To achieve the above object, the technical solution of the present invention is as follows:

A prednisolone enteric-coated sustained-release tablet comprises a single-layer tablet core containing prednisolone and an enteric coating film, wherein the components of the single-layer tablet core comprise prednisolone, a sustained-release skeleton material, a release regulator, and an adhesive; the enteric coating film is obtained by coating the surface of the single-layer tablet core with an enteric coating liquid comprising an enteric material, an anti-adhesive agent, and a plasticizer, wherein the components of the single-layer tablet core may or may not include other pharmaceutically acceptable additives as required.

Preferably, the additive is a glidant.

Preferably, the weight of the enteric coating film accounts for 3%-10% of the weight of the single-layer tablet core, preferably 5.6%-9.1%.

Preferably, the single-layer tablet core comprises the following components in weight percentage: 15%-35% of prednisolone, 8%-35% of sustained-release matrix material, 30%-70% of release regulator, 1%-5% of binder, 0%-5% of glidant, preferably 20%-30% of prednisolone, 8%-25% of sustained-release matrix material, 40%-67% of release regulator, 14% of binder, and 1.3% of glidant;

Preferably, the amount of the anti-adhesive agent is 60%-80% of the mass of the enteric material, and the amount of the plasticizer is 5%-10% of the mass of the enteric material. More preferably, the amount of the anti-adhesive agent is 60%-62.5% of the mass of the enteric material, and the amount of the plasticizer is 8.75%-10% of the mass of the enteric material.

More preferably, the single-layer tablet core comprises the following components in weight percentage: 20%-30% prednisolone, 8%-25% high viscosity hydroxypropyl methylcellulose (preferably hydroxypropyl methylcellulose K4M), 40%-67% release modifier lactose, 4% binder povidone, and 1.3% glidant magnesium stearate;

More preferably, the enteric material is methacrylic acid-ethyl acrylate copolymer (more preferably Eudragit L30D-55), the anti-adhesive agent is talc, and the plasticizer is polyethylene glycol.

The present invention also provides a method for preparing the above-mentioned prednisolone enteric-coated sustained-release tablets, and the specific preparation process is as follows:

(1) Preparation of single-layer tablet core:

Prednisolone is mixed evenly with a sustained-release skeleton material, a release regulator, and a binder, and water is added to make a soft material, followed by granulation and drying, and then additives are added as needed, mixed evenly, and pressed into tablets to obtain a single-layer tablet core;

(2) Enteric coating:

After the anti-adhesive agent is evenly dispersed in water, a plasticizer is added thereto, stirred evenly, and then an enteric material is added thereto to form an enteric coating solution. The single-layer tablet core obtained in step (1) is placed in a coating pan, heated evenly, and then coated with the enteric coating solution. After the coating is completed, an enteric coating film is formed on the surface, which is dried to obtain prednisolone enteric-coated sustained-release tablets.

Preferably, the drying conditions in step (1) are: controlling the moisture content at 3%-5%; the tableting control conditions are: using a rotary tablet press to press the tablets according to a theoretical tablet weight of 150 mg, and adjusting the tableting pressure during the tableting process to ensure that the hardness of the tablets is controlled at 5-10 kg.

Compared with the prior art, the advantages and beneficial effects of the present invention are as follows:

The present invention uses a suitable dose of hypromellose K4M as a sustained-release material, which can continuously release drugs for 24 hours, thereby extending the drug's action time, reducing the frequency of administration, improving patient compliance, and reducing adverse drug reactions. In addition, the preparation method is simple and easy to implement, and is suitable for large-scale production.

The sustained-release tablets of the present invention are taken once a day, have a higher drug loading than a single dose of a traditional dosage form drug, and can maintain an effective blood drug concentration for a long time, greatly reducing the fluctuation of blood drug concentration, allowing the human body to obtain a stable and effectively therapeutic blood drug concentration, thereby ensuring the therapeutic effect of the drug.

Detailed ways

The beneficial effects of the present invention are now described through the following specific implementations, but this should not be understood as the scope of the above subject matter being limited to the following embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

The raw and auxiliary materials used in the following examples are all purchased commercial products, wherein lactose refers to lactose monohydrate; and the polyethylene glycol is polyethylene glycol 400.

Example 1 Prednisolone enteric-coated sustained-release tablets were prepared according to the following components (each tablet contained 30 mg of the main drug per tablet, and a total of 1000 tablets were prepared):

Single-layer core:

Table 1

Enteric coating film:

Table 2

The specific preparation method is as follows:

(1) Prednisolone, hydroxypropyl methylcellulose (K4M), lactose, and povidone (K30) are crushed separately, passed through a 100-mesh sieve, added to a wet granulator and mixed for 5 minutes until the mixture is uniform, and an appropriate amount of purified water is slowly added to form a soft material. The soft material is granulated after passing through a 16-mesh sieve, and then dried in an oven at 60° C. The moisture content is controlled between 3% and 5%. The resulting dry granules are passed through a 1.0 mm sieve. Magnesium stearate is then added to the above-mentioned sieved dry granules, and the mixture is continued to be mixed in a granulator for 5 minutes until the mixture is uniform. Finally, a rotary tablet press is used to press the tablets according to a theoretical tablet weight of 150 mg. During the tableting process, the tableting pressure is adjusted to ensure that the hardness of the tablets is controlled between 5 and 8 kg (using a hardness tester to test the hardness), and a single-layer tablet core is obtained.

(2) Disperse 3 g of talc in 49 g of purified water, stir evenly, add 0.5 g of polyethylene glycol, and continue stirring evenly to obtain a suspension. Add the above suspension to 5 g of Eudragit L30 D-55, stir evenly to obtain an enteric coating solution.

(3) placing all the single-layer tablet cores obtained in step (1) in a coating pan, heating them evenly, adding the enteric coating solution of step (2) for coating, and drying after completion to obtain prednisolone enteric-coated sustained-release tablets.

Example 2 Prednisolone enteric-coated sustained-release tablets were prepared according to the following components (each tablet contained 45 mg of the main drug per tablet, and a total of 1000 tablets were prepared):

Single-layer core:

table 3

Prednisolone 45g Hydroxypropyl methylcellulose K4M 37.5g lactose 59.5g Povidone K30 6g Magnesium stearate 2g

Enteric coating film:

Table 4

Utech L30D-55 5g talcum powder 3g Polyethylene glycol 0.5g

The preparation method is the same as that in Example 1, except that the hardness of the tablets is controlled to be 6-10 kg during tableting in this embodiment, and the other steps are the same as those in Example 1 to prepare prednisolone enteric-coated sustained-release tablets.

Example 3: Prednisolone enteric-coated sustained-release tablets were prepared according to the following components (each tablet contained 30 mg of the main drug, and a total of 1000 tablets were prepared):

Single layer core

table 5

Prednisolone 30g Hydroxypropyl methylcellulose K4M 12g lactose 100g Povidone K30 6g Magnesium stearate 2g

Enteric coating film:

Table 6

Utech L30D-55 5g talcum powder 3g Polyethylene glycol 0.5g

The preparation method is the same as that in Example 1 to prepare prednisolone enteric-coated sustained-release tablets.

Example 4 Prednisolone enteric-coated sustained-release tablets were prepared according to the following components (each tablet contained 30 mg of the main drug per tablet, and a total of 1000 tablets were prepared):

Single-layer core:

Table 7

Prednisolone 30g Hydroxypropyl methylcellulose K4M 22g lactose 90g Povidone K30 6g Magnesium stearate 2g

Enteric coating film:

Table 8

Utech L30D-55 8g talcum powder 5g Polyethylene glycol 0.7g

The preparation method is the same as that in Example 1, except that in this example, talcum powder is dispersed in 78 g of purified water, and the other steps are the same as those in Example 1 to prepare prednisolone enteric-coated sustained-release tablets.

Comparative Example 1

Preparation of prednisolone tablets (each tablet contains 5 mg of the main drug, a total of 1000 tablets):

According to the reference preparation catalogue published by NMPA, the information of the reference preparation - Prednisolone Tablets was found: the active substance is prednisolone contained in each tablet at 2.5 mg, 5 mg and 10 mg respectively.

The other ingredients are lactose monohydrate 70 mg, magnesium stearate, gelatin, microcrystalline cellulose, talc and potato starch, as shown in Table 9.

Table 9

Prednisolone Lactose Monohydrate Potato starch gelatin Microcrystalline cellulose talcum powder Magnesium stearate 5g 70g 20g 3g 50g 1g 1g

Preparation process: Weigh the prescribed amount of prednisolone, lactose monohydrate, potato starch, and microcrystalline cellulose and mix them in a wet granulator for 5 minutes. Use gelatin aqueous solution to make soft material, pass through an 18-mesh screen for granulation, place the wet granules on a tray, dry them in a 60°C forced air drying oven, and control the moisture content to 3% to 5%; pass the dry granules through a 24-mesh screen for granulation; after granulation, put the granules into a three-dimensional motion mixer, add the prescribed amount of magnesium stearate and talcum powder and mix for 5 minutes; use a rotary tablet press to compress the tablets according to the theoretical tablet weight of 150 mg, adjust the tableting pressure, and control the tablet hardness to 5 to 8 kg.

The release rate of the products obtained in the above Examples 1-4 and Comparative Example 1 was measured.

Preparation of test samples for the product of comparative example 1:

Method: Take this product and adopt the second method (paddle method) of release determination method (General Rule 0931 of Part IV of the 2020 edition of the Chinese Pharmacopoeia), use 900ml of phosphate buffer solution with pH=6.8 at 37℃, and the speed is 50rpm. Other release experiments are carried out in accordance with the requirements of the Pharmacopoeia. Take 5ml of the solution at the specified time points for filtration, and add 5ml of the same solvent in the operating container in time.

Preparation of test samples for the products of Examples 1, 2, 3, and 4:

Method: Take this product and adopt the second method (paddle method) of the release determination method (General Rules 0931 of Part IV of the 2020 edition of the Chinese Pharmacopoeia), with 900ml of 0.1mol/l hydrochloric acid solution as the solvent, the speed is 100 revolutions per minute, after 120 minutes, discard the acidic solution, wash the solution attached to the surface of the tablet with water, replace the medium in the dissolution cup with 900ml of 37℃ pH=6.8 phosphate buffer, the speed is 50rpm, and continue to release, and the rest is in accordance with the requirements of the pharmacopoeia. Take 5ml of the solution at the specified time point for filtration, and add 5ml of the same solvent in the operation container in time.

Detection method: After the test sample is prepared, it is tested according to the UV-visible light photometry method to calculate the cumulative release of the tablets. The calculation formula is as follows:

The results are shown in Table 10.

Table 10

It can be seen from the data in Table 10 that the samples prepared in Examples 1-4 of the present invention can be continuously released within 24 hours; at the same time, reducing the amount of hydroxypropyl methylcellulose K4M can still release the drug continuously, and the release rate increases after the amount of hydroxypropyl methylcellulose K4M is reduced; and increasing the amount of prednisolone and hydroxypropyl methylcellulose K4M can still release the drug continuously, and the release rate decreases after the amount of hydroxypropyl methylcellulose K4M is increased; in Example 4, increasing the weight of the enteric coating film in each sustained-release tablet (i.e., increasing the weight of the enteric coating film relative to the tablet core after coating and drying, the weight of the enteric coating film in the embodiment is 5.6% to 9.1% of the weight of the single-layer tablet core), the drug can still be released continuously, and the release rate decreases.

Claims (9)

1. The prednisone Long Chang soluble sustained-release tablet comprises a single-layer tablet core containing prednisolone and an enteric coating film, wherein the single-layer tablet core comprises the prednisolone, a sustained-release framework material, a release regulator and an adhesive; the enteric coating film is obtained by coating an enteric coating solution consisting of an enteric material, an anti-adhesion agent and a plasticizer on the surface of a single-layer tablet core, wherein other pharmaceutically acceptable additives can be included or not included in the components of the single-layer tablet core according to the needs.

2. The prednisone Long Chang soluble sustained release tablet of claim 1, wherein said additive is a glidant.

3. The prednisone Long Chang soluble sustained release tablet of claim 2, wherein said single layer tablet core comprises the following components in weight percent: 15-35% of prednisolone, 8-35% of slow-release framework material, 30-70% of release regulator, 1-5% of adhesive and 0-5% of glidant.

4. The prednisone Long Chang soluble sustained release tablet of claim 3, wherein said single layer tablet core comprises the following components in weight percent: 20-30% of prednisolone, 8-25% of high-viscosity hypromellose, 40-67% of release regulator lactose, 4% of adhesive povidone and 1.3% of glidant magnesium stearate.

5. The prednisone Long Chang soluble sustained release tablet according to claim 1, wherein the weight of the enteric coating film is 3% -10% of the weight of the single-layer tablet core.

6. The prednisone Long Chang soluble sustained release tablet according to claim 5, wherein the dosage of the anti-sticking agent is 60-80% of the mass of the enteric material, and the dosage of the plasticizer is 5-10% of the mass of the enteric material.

7. The prednisone Long Chang soluble and slow release tablet of claim 6, wherein said enteric material is methacrylic acid-ethyl acrylate copolymer, said anti-sticking agent is talc, and said plasticizer is polyethylene glycol 400.

8. A method for preparing a prednisone Long Chang sustained-release tablet according to any one of claims 1 to 7, which is characterized by comprising the following specific steps:

(1) Preparation of a single-layer core:

mixing prednisolone with slow release skeleton material, release regulator and binder, adding water to obtain soft material, granulating, drying, adding additives as required, mixing, and tabletting to obtain single-layer tablet core;

(2) Enteric coating:

dispersing the anti-sticking agent in water uniformly, adding a plasticizer into the water, stirring the mixture uniformly, adding an enteric material into the mixture to form an enteric coating liquid, placing the single-layer tablet core obtained in the step (1) into a coating pot, heating the mixture uniformly, coating the tablet core with the enteric coating liquid, forming an enteric coating film on the surface after coating, and drying the coated tablet core to obtain the prednisone Long Chang sustained-release tablet.

9. The method according to claim 8, wherein the drying conditions in the step (1) are: controlling the water content to be 3% -5%; the control conditions of the pressed tablet are as follows: and (3) tabletting according to the theoretical tablet weight of 150mg by using a rotary tabletting machine, and adjusting the tabletting pressure in the tabletting process to ensure that the hardness of the tablets is controlled to be 5-10 kg.