Piribedil sustained-release tablet and preparation method thereof

Abstract

The present invention relates to the technical field of pharmaceutical preparations, and specifically discloses a piribedil sustained-release tablet and a preparation method thereof. The piribedil sustained-release tablet comprises a tablet core and a coating layer, wherein the tablet core comprises piribedil, a sustained-release material, an adhesive, and a lubricant; the sustained-release material is selected from at least one of glyceryl behenate, hydrogenated oil, or talc; and the coating layer comprises a water-soluble coating material and a water-insoluble coating material. The sustained-release material is prepared into uniform hydrophobic dry granules by granulation, and then the piribedil raw material is mixed with sustained-release granules of a specific particle size so that the main drug is embedded in the gaps between the sustained-release granules, and then tableting is performed to prepare the tablet core. During the preparation process, the influence of temperature and humidity on the piribedil raw material is avoided, and the impurity stability during the preparation process is significantly improved. The dissolution curve of the prepared piribedil sustained-release tablet is similar to that of the original preparation, and the original product can be replaced.

Description

Technical Field

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

[0002] Piribedil, chemically known as [(methylenedioxy-3,4)-4-piperazinyl-1]-2-pyrimidine, was developed by Servier in France. It is a dopamine agonist that stimulates postsynaptic D2 receptors in the nigrostriatum and D2 and D3 receptors in the midbrain cortex and mesolimbic pathways, providing a potent dopamine effect. It is used as a monotherapy or in combination with levodopa to treat Parkinson's disease. The original formulation was developed as a sustained-release, sugar-coated tablet, marketed as Tayson. The sugar coating increased the weight by 58.5%, and the tablet contained a large amount of sucrose, making it a "sugar bomb" for Parkinson's patients with fructose intolerance, glucose or galactose malabsorption syndrome, or sucrase-isomaltase deficiency. Tayson can be used as a monotherapy or in combination with levodopa, and sales are optimistic. Therefore, it is of great significance to develop a piribedil sustained-release tablet, which is a film-coated sustained-release tablet with the same quality as the original research, to fill the gap in domestic medication.

[0003] Existing piribedil sustained-release tablets use expensive hydrophilic gel matrix materials such as hypromellose for their sustained-release materials, with imported hypromellose being even more expensive. Some existing piribedil sustained-release tablets are prepared as piribedil tablets, while others are prepared as piribedil coated tablets. Whether these tablets or coated tablets, it is difficult to achieve a release curve with the same drug release rate as the original sugar-coated tablets, with release rates varying between faster and slower. Furthermore, tablets prepared by wet granulation suffer from relatively poor quality stability. Currently, the only piribedil sustained-release tablet on the market in China is the original formulation, and no pharmaceutical company has applied for generic approval. Therefore, developing a low-cost piribedil sustained-release tablet that is consistent with the original product and highly stable is of great significance. Summary of the Invention

[0004] Aiming at the problems that existing piribedil tablets have poor consistency with original research, stability needs to be further improved, and preparation cost is high, the present invention provides a piribedil sustained-release tablet and a preparation method thereof.

[0005] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0006] A piribedil sustained-release tablet comprises a tablet core and a coating layer, wherein the tablet core comprises piribedil, a sustained-release material, a binder and a lubricant; wherein the sustained-release material is selected from at least one of glyceryl behenate, hydrogenated oil or talc; and the coating layer comprises a water-soluble coating material and a water-insoluble coating material.

[0007] Compared with the prior art, the piribedil sustained-release tablets provided by the present invention achieve effective regulation of the drug release rate of the piribedil sustained-release tablets by selecting a water-soluble coating material and a water-insoluble coating material as a mixed coating system, and combining them with a specific sustained-release material, so that the prepared piribedil sustained-release tablets have release characteristics similar to those of the original formulation, solving the problem of excessively fast or slow release of the existing piribedil sustained-release tablets. In addition, the drug has high stability, can better exert the efficacy of the piribedil sustained-release tablets, and improves its drug effectiveness, thereby effectively replacing the original product. In addition, the sustained-release material selected by the present invention is low in price. While ensuring similarity to the original product and improving drug stability, the production cost of the piribedil sustained-release tablets is also effectively reduced, and the market prospect is broad.

[0008] Preferably, the core tablet comprises the following components in weight percentage: 20%-30% of piribedil, 65%-70% of sustained-release material, 4%-8% of binder and 0.5%-2.0% of lubricant.

[0009] Preferably, the D10 of the piribedil is 55 μm-90 μm, the D50 is 90 μm-125 μm, and the D90 is 125 μm-350 μm.

[0010] The preferred particle size distribution of the piribedil raw material can make the piribedil raw material and the excipients uniformly mixed, so that the release rate of the prepared piribedil sustained-release tablets is consistent with that of the original formulation, thereby improving the similarity between the piribedil sustained-release tablets and the original formulation.

[0011] Preferably, the sustained-release material is talc.

[0012] Choosing the low-cost hydrophobic excipient talc as the sustained-release material can not only reduce the preparation cost, but also make the prepared piribedil sustained-release tablets have the same release rate as the original formulation, thereby improving the similarity with the original formulation.

[0013] Preferably, the binder is at least one of carboxymethyl cellulose, povidone, xanthan gum or gum arabic.

[0014] Preferably, the lubricant is at least one of magnesium stearate, calcium stearate or sodium stearyl fumarate.

[0015] The preferred lubricant can improve the compressibility of the material, reduce the dosage deviation of the piribedil raw material, promote the disintegration and dissolution of piribedil, and achieve a dissolution curve consistent with that of the original preparation.

[0016] Preferably, the mass ratio of the water-soluble coating material to the water-insoluble coating material is 4:6-2:8.

[0017] Preferably, the water-soluble coating material is one or both of HPMC coating powder and PVA coating powder.

[0018] Preferably, the water-insoluble coating material is one or both of Eudragit RS30D aqueous dispersion and Eudragit RL30D aqueous dispersion.

[0019] More preferably, the water-soluble coating material is HPMC coating powder, and the water-insoluble coating material is Eudragit RL30D aqueous dispersion. More preferably, the water-soluble coating material is HPMC-type Opadry coating powder.

[0020] By using a mixed coating system composed of a specific ratio of water-soluble coating materials and water-insoluble coating materials, the film-coated tablets achieve release characteristics similar to those of the original sugar-coated tablets, solving the problem of faster or slower release of existing piribedil tablets, and facilitating the effective replacement of the original product.

[0021] Furthermore, the solid content of the Eudragit RS30D aqueous dispersion or the Eudragit RL30D aqueous dispersion is 30%.

[0022] Preferably, the coating layer accounts for 15%-30% of the mass of the tablet core.

[0023] The sustained-release material of the present invention uses inexpensive talcum powder, and replaces the original sugar coating with a mixed coating system of a water-soluble coating material and a water-insoluble coating material. This not only avoids the problem of being unsuitable for Parkinson's patients with fructose intolerance, glucose or galactose malabsorption syndrome, or sucrase-isomaltase deficiency, but also achieves a drug release rate similar to that of the original drug. At the same time, the drug stability is also improved, making it a better alternative to the original drug.

[0024] The present invention also provides a method for preparing piribedil sustained-release tablets, comprising the following steps:

[0025] S1, dissolving a binder in water to obtain a binder solution; spraying the binder solution onto the surface of a sustained-release material, wet granulating, drying, and sieving to obtain sustained-release granules;

[0026] S2, mixing the piribedil raw material and the sustained-release granules uniformly, adding a lubricant, mixing uniformly, and tableting to obtain tablet cores;

[0027] S3, adding a water-soluble coating material into water to obtain a water-soluble coating solution; adding the water-soluble coating solution into a water-insoluble coating material, mixing them evenly to obtain a mixed coating system; coating the tablet core with the mixed coating system to obtain piribedil sustained-release tablets.

[0028] The preparation method of the piribedil sustained-release tablets provided by the present invention comprises the following steps: preparing a sustained-release material into uniform hydrophobic dry granules by granulation; then mixing the piribedil raw material with sustained-release granules of a specific particle size; embedding the main drug in the gaps between the sustained-release granules; and then performing tablet compression to prepare tablet cores. During the preparation process, the influence of temperature and humidity on the piribedil raw material is avoided, and the impurity stability during the preparation process is significantly improved. Moreover, the dissolution curve of the prepared piribedil sustained-release tablets is similar to that of the original preparation, and the original product can be replaced.

[0029] Preferably, in S1, the mass concentration of the adhesive solution is 5%-8%.

[0030] Preferably, in S1, the spraying time is 2 min-3 min, the stirring speed during the spraying process is 80 rpm-150 rpm, and the chopping speed is 1000 rpm-1800 rpm.

[0031] Preferably, in S1, the particle size of the sustained-release granules is 40 mesh to 150 mesh.

[0032] Preferably, in S2, the hardness of the tablet is 40N-80N.

[0033] Exemplarily, in S2, an 8 mm shallow concave punch is selected for tableting.

[0034] Preferably, in S3, the coating weight gain is 15%-30%.

[0035] Furthermore, in S3, the water-soluble coating material is first added to water to prepare a coating solution with a solid content of 10%-15%, and then the coating solution is added to the water-insoluble coating material and mixed evenly to obtain a mixed coating system.

[0036] Compared with sugar coating, the film coating provided by the present invention has the advantages of fewer types of coating materials, simple preparation and operation, simple coating process, small coating weight gain, short coating process time, low production cost, and the prepared coated tablets have a smooth and bright appearance, are strong, and are not easy to crack.

[0037] The piribedil sustained-release tablets provided by the present invention effectively improve the drug release rate of the piribedil sustained-release tablets by selecting specific sustained-release materials and coating materials, controlling the particle size distribution of the piribedil raw material, and coordinating a process of granulating the sustained-release material separately and then directly mixing it with the piribedil raw material. The in vitro dissolution curve of the prepared piribedil is consistent with that of the original preparation, and the impurity content is lower, the stability is good, the safety of clinical application is improved, and the market prospect is broad. DETAILED DESCRIPTION

[0038] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0039] In order to better illustrate the present invention, further examples are given below.

[0040] The particle size distribution of the piribedil raw material used in the following examples and comparative examples is: D10 is 55 μm-90 μm, D50 is 90 μm-125 μm, and D90 is 125 μm-350 μm.

[0041] Example 1

[0042] This embodiment provides a piribedil sustained-release tablet, and the dosage of the prescription (1000 tablets) is shown in the following table:

[0043]

[0044]

[0045] The preparation method of the above-mentioned piribedil sustained-release tablets comprises the following steps:

[0046] S1, preparing sustained-release granules: adding gum arabic to water to prepare a 5% mass concentration gum arabic solution; adding talc to a wet mixing granulation pot, and spraying the gum arabic solution evenly onto the surface of the talc using a spray gun. The spraying time is 2 minutes, the stirring speed is 150 rpm, and the chopping speed is 1000 rpm. After the spraying is completed, granulation is continued for 2 minutes, the material is discharged, dried, sieved, and 40-150 mesh granules are collected to obtain sustained-release granules;

[0047] S2, preparing tablet cores: mixing the prescribed amount of piribedil raw material with the above-mentioned sustained-release granules, mixing for 15 minutes, adding magnesium stearate, continuing to mix for 5 minutes, discharging, and tableting to obtain tablet cores; using an 8mm shallow concave punch for tableting, the tableting hardness is controlled at 70-80N;

[0048] S3. Preparation of coated tablets: HPMC Opadry coating powder was prepared into a 13% HPMC Opadry coating powder solution in 50 g of purified water. The solution was then slowly added to 100 g of Eudragit RL30D aqueous dispersion (30% solids content, 30 g on a dry basis) and stirred for 30 min to obtain a mixed coating system. 250 g of core tablets were coated to a coating weight gain of 15%.

[0049] Example 2

[0050] This embodiment provides a piribedil sustained-release tablet, and the dosage of the prescription (1000 tablets) is shown in the following table:

[0051]

[0052]

[0053] The preparation method of the above-mentioned piribedil sustained-release tablets comprises the following steps:

[0054] S1, preparing sustained-release granules: adding gum arabic to water to prepare a gum arabic solution with a mass concentration of 8%; adding talc to a wet mixing granulation pot, and spraying the gum arabic solution evenly onto the surface of the talc using a spray gun. The spraying time is 3 minutes, the stirring speed is 80 rpm, and the chopping speed is 1800 rpm. After the spraying is completed, granulation is continued for 2 minutes. The material is discharged, dried, sieved, and 40-150 mesh granules are collected to obtain sustained-release granules;

[0055] S2, preparing tablet cores: mixing the prescribed amount of piribedil raw material with the above-mentioned sustained-release granules, mixing for 15 minutes, adding magnesium stearate, continuing to mix for 5 minutes, discharging, and tableting to obtain tablet cores; using an 8mm shallow concave punch for tableting, the tableting hardness is controlled at 40-50N;

[0056] S3. Preparation of coated tablets: HPMC Opadry coating powder was prepared into a 13% HPMC Opadry coating powder solution in 200 g of purified water. The solution was then slowly added to 150 g of Eudragit RL30D aqueous dispersion (30% solids content, 45 g on a dry basis) and stirred for 30 min to obtain a mixed coating system. 250 g of core tablets were coated to a coating weight gain of 30%.

[0057] Example 3

[0058] This embodiment provides a piribedil sustained-release tablet, and the dosage of the prescription (1000 tablets) is shown in the following table:

[0059]

[0060]

[0061] The preparation method of the above-mentioned piribedil sustained-release tablets comprises the following steps:

[0062] S1, preparing sustained-release granules: adding gum arabic to water to prepare a 6% mass concentration gum arabic solution; adding talc to a wet mixing granulation pot, and spraying the gum arabic solution evenly onto the surface of the talc using a spray gun. The spraying time is 3 minutes, the stirring speed is 120 rpm, and the chopping speed is 1500 rpm. After the spraying is completed, granulation is continued for 2 minutes. The material is discharged, dried, sieved, and 40-150 mesh granules are collected to obtain sustained-release granules;

[0063] S2, preparing tablet cores: mixing the prescribed amount of piribedil raw material with the above-mentioned sustained-release granules, mixing for 15 minutes, adding magnesium stearate, continuing to mix for 5 minutes, discharging, and tableting to obtain tablet cores; using an 8mm shallow concave punch for tableting, the tableting hardness is controlled at 50-60N;

[0064] S3. Preparation of coated tablets: HPMC Opadry coating powder was prepared into a 13% HPMC Opadry coating powder solution in 100 g of purified water. The solution was then slowly added to 116.7 g of Eudragit RL30D aqueous dispersion (30% solids content, 35 g on a dry basis) and stirred for 30 min to obtain a mixed coating system. 250 g of core tablets were coated to a coating weight gain of 20%.

[0065] Example 4

[0066] This embodiment provides a piribedil sustained-release tablet, which differs from Example 3 only in that Eudragit RL30D aqueous dispersion is replaced with Eudragit RS30D aqueous dispersion. The specific prescription (1000 tablets) and dosage are shown in the following table:

[0067]

[0068]

[0069] The preparation method of the above-mentioned piribedil sustained-release tablets comprises the following steps:

[0070] S1, preparing sustained-release granules: adding gum arabic to water to prepare a 6% mass concentration gum arabic solution; adding talc to a wet mixing granulation pot, and spraying the gum arabic solution evenly onto the surface of the talc using a spray gun. The spraying time is 3 minutes, the stirring speed is 120 rpm, and the chopping speed is 1500 rpm. After the spraying is completed, granulation is continued for 2 minutes. The material is discharged, dried, sieved, and 40-150 mesh granules are collected to obtain sustained-release granules;

[0071] S2, preparing tablet cores: mixing the prescribed amount of piribedil raw material with the above-mentioned sustained-release granules, mixing for 15 minutes, adding magnesium stearate, continuing to mix for 5 minutes, discharging, and tableting to obtain tablet cores; using an 8mm shallow concave punch for tableting, the tableting hardness is controlled at 50-60N;

[0072] S3. Preparation of coated tablets: HPMC Opadry coating powder was prepared into a 13% HPMC Opadry coating powder solution in 100 g of purified water. The solution was then slowly added to 116.7 g of Eudragit RS30D aqueous dispersion (30% solids content, 35 g on a dry basis) and stirred for 30 min to obtain a mixed coating system. 250 g of core tablets were coated to a coating weight gain of 20%.

[0073] Comparative Example 1

[0074] This comparative example provides a method for preparing piribedil sustained-release tablets. The only difference between the prescription and that of Example 3 is that talc is replaced with an equal amount of hypromellose (model K100M). Piribedil sustained-release tablets are prepared according to the same process as in Example 3.

[0075] The prescription of described Piribedil sustained-release tablets (1000 tablets) is as follows:

[0076]

[0077]

[0078] The results showed that during the granulation process, granulation was difficult, the process was not smooth, the granules could not be smoothly granulated, and the subsequent tableting and coating could not be carried out smoothly.

[0079] Comparative Example 2

[0080] This comparative example provides a method for preparing piribedil sustained-release tablets. The prescription of this comparative example is exactly the same as that of Example 3 and will not be repeated here. A wet granulation process is adopted, and the specific process steps are as follows:

[0081] S1, preparing tablet cores: adding gum arabic to water to prepare a 6% mass concentration gum arabic solution; adding piribedil raw material and talc into a wet mixing granulation pot, spraying the gum arabic solution evenly onto the surface of the talc using a spray gun, spraying for 3 minutes, stirring at 120 rpm, and chopping at 1500 rpm. After spraying, granulation is continued for 2 minutes, the material is discharged, dried, sieved, and 40-150 mesh granules are collected. Magnesium stearate is then added and mixing is continued for 5 minutes. The material is discharged and tableted to obtain tablet cores; an 8 mm shallow concave punch is used for tableting, and the tableting hardness is controlled to 50-60N;

[0082] S2. Preparation of coated tablets: HPMC Opadry coating powder was prepared into a 13% HPMC Opadry coating powder solution in 100 g of purified water. The solution was then slowly added to 116.7 g of Eudragit RL30D aqueous dispersion (30% solids content, 35 g on dry basis) and stirred for 30 min to obtain a mixed coating system. 250 g of core tablets were coated to a coating weight gain of 20%.

[0083] Comparative Example 3

[0084] This comparative example provides a method for preparing piribedil sustained-release tablets. The only difference between the formulation and that of Example 3 is that the Eudragit RL30D aqueous dispersion is replaced with an equal amount of HPMC-type Opadry coating powder. That is, only HPMC-type Opadry coating powder is used as the coating material. The specific formulation (1000 tablets) and dosage are shown in the following table:

[0085] Tablet prescription: Components Dosage Piribedil 62.5g talcum powder 171.25g Gum Arabic 15g magnesium stearate 1.25g Film coating formulation Components Dosage HPMC type Opadry coating powder 50g purified water 335g

[0086] The preparation method of the above-mentioned piribedil sustained-release tablets comprises the following steps:

[0087] S1, preparing sustained-release granules: adding gum arabic to water to prepare a 6% mass concentration gum arabic solution; adding talc to a wet mixing granulation pot, and spraying the gum arabic solution evenly onto the surface of the talc using a spray gun. The spraying time is 3 minutes, the stirring speed is 120 rpm, and the chopping speed is 1500 rpm. After the spraying is completed, granulation is continued for 2 minutes. The material is discharged, dried, sieved, and 40-150 mesh granules are collected to obtain sustained-release granules;

[0088] S2, preparing tablet cores: mixing the prescribed amount of piribedil raw material with the above-mentioned sustained-release granules, mixing for 15 minutes, adding magnesium stearate, continuing to mix for 5 minutes, discharging, and tableting to obtain tablet cores; using an 8mm shallow concave punch for tableting, the tableting hardness is controlled at 50-60N;

[0089] S3, preparing coated tablets: 50 g of HPMC Opadry coating powder was prepared into a 13% HPMC Opadry coating powder solution with purified water, and 250 g of tablet cores were coated with the solution to a coating weight gain of 20%.

[0090] Comparative Example 4

[0091] This comparative example provides a method for preparing piribedil sustained-release tablets. The only difference between the prescription and that of Example 3 is that the HPMC-type Opadry coating powder is replaced with an equal amount of Eudragit RL30D aqueous dispersion, that is, only Eudragit RL30D aqueous dispersion is used as the coating material. The specific prescription (1000 tablets) and dosage are shown in the following table:

[0092] Tablet prescription: Components Dosage Piribedil 62.5g talcum powder 171.25g Gum Arabic 15g magnesium stearate 1.25g Film coating formulation Components Dosage Eudragit RL30D aqueous dispersion 50g

[0093] The preparation method of the above-mentioned piribedil sustained-release tablets comprises the following steps:

[0094] S1, preparing sustained-release granules: adding gum arabic to water to prepare a 6% mass concentration gum arabic solution; adding talc to a wet mixing granulation pot, and spraying the gum arabic solution evenly onto the surface of the talc using a spray gun. The spraying time is 3 minutes, the stirring speed is 120 rpm, and the chopping speed is 1500 rpm. After the spraying is completed, granulation is continued for 2 minutes. The material is discharged, dried, sieved, and 40-150 mesh granules are collected to obtain sustained-release granules;

[0095] S2, preparing tablet cores: mixing the prescribed amount of piribedil raw material with the above-mentioned sustained-release granules, mixing for 15 minutes, adding magnesium stearate, continuing to mix for 5 minutes, discharging, and tableting to obtain tablet cores; using an 8mm shallow concave punch for tableting, the tableting hardness is controlled at 50-60N;

[0096] S3, preparing coated tablets: taking 166.7 g of Eudragit RL30D aqueous dispersion (solid content 30%, 50 g on dry basis), taking 250 g of core tablets for coating, and the coating weight gain was 20%.

[0097] Comparative Example 5

[0098] This comparative example provides a method for preparing piribedil sustained-release tablets. The prescription of this comparative example is exactly the same as that of Example 3 and will not be repeated here. The piribedil raw material is micronized and the raw material with D10 <15 μm, D50 <25 μm, and D90 <55 μm is used to prepare the preparation. The specific process steps are as follows:

[0099] S1, preparing sustained-release granules: adding gum arabic to water to prepare a 6% mass concentration gum arabic solution; adding talc to a wet mixing granulation pot, and spraying the gum arabic solution evenly onto the surface of the talc using a spray gun. The spraying time is 3 minutes, the stirring speed is 120 rpm, and the chopping speed is 1500 rpm. After the spraying is completed, granulation is continued for 2 minutes. The material is discharged, dried, sieved through a 0.8 mm sieve, and sieved to obtain sustained-release granules;

[0100] S2, preparing tablet cores: the prescribed amount of piribedil raw material is mixed with the above-mentioned sustained-release granules of 150 mesh or less, 100 mesh or less, 80 mesh or less, 60 mesh or less, 40 mesh or less, and the remaining granules in equal amounts, and magnesium stearate is added after the mixing is completed. The mixture is continued to mix for 5 minutes, and the material is discharged and tableted to obtain tablet cores; an 8 mm shallow concave punch is used for tableting, and the tableting hardness is controlled to 50-60N;

[0101] S3. Prepare a 13% HPMC Opadry coating powder solution in 100 g of purified water. This solution is then added to 116.7 g of Eudragit RL30D aqueous dispersion (30% solids, 35 g on a dry basis) and stirred for 30 min to obtain a mixed coating system. 250 g of core tablets are coated to a coating weight gain of 20%.

[0102] Comparison of in vitro dissolution behavior

[0103] According to the "Guidelines for Determination and Comparison of Dissolution Curves of Ordinary Oral Solid Preparations" issued by the CDE, referring to the release method of the import registration standard JX20030158, the paddle method was 100rpm, the medium was 1000mL, pH1.0 hydrochloric acid medium, pH4.5 acetate medium and pH6.8 phosphate medium, and the sampling time points were 1h, 2h, 4h, 6h, 8h, 12h, 16h, and 24h, and the cumulative dissolution at each time point was detected (HPLC method). The average cumulative dissolution results of 12 tablets are shown in Tables 1-3. Among them, the original research is an imported drug from ES LABORATOIRESSERVIER, which is the reference preparation announced by the state, batch number: 6049705.

[0104] Table 1: Cumulative dissolution in hydrochloric acid medium at pH 1.0 (%)

[0105]

[0106]

[0107] Table 2: Cumulative dissolution in pH 4.5 acetate medium (%)

[0108] sample 1h 2h 4h 6h 8h 12h 16h 24h f2 Example 1 1.3 3.6 8.7 12.0 16.9 24.2 31.6 43.2 94 Example 2 2.1 5.0 9.8 15.0 18.9 26.8 34.1 46.9 94 Example 3 1.8 4.6 9.7 13.6 18.0 25.3 33.0 45.0 99 Example 4 1.1 3.2 8.1 11.8 15.8 22.8 30.5 42.0 88 Original research 1.6 4.0 9.1 13.7 17.9 25.5 32.7 45.4 —

[0109] Table 3: Cumulative dissolution in pH 6.8 phosphate medium (%)

[0110] sample 1h 2h 4h 6h 8h 12h 16h 24h f2 Example 1 1.9 2.8 4.3 5.4 6.6 8.3 10.4 13.1 95 Example 2 3.0 3.9 5.8 7.1 8.2 9.9 12.0 16.3 97 Example 3 2.5 3.5 5.4 6.5 7.5 9.5 11.1 14.7 100 Example 4 1.4 2.5 4.0 5.1 6.0 7.9 10.1 11.7 92 Original research 2.4 3.5 5.2 6.4 7.4 9.3 11.0 14.5 —

[0111] A similarity factor f2>50 is considered similar, and the larger the f2 value, the better the similarity. As can be seen from the data in the above table, the release behaviors of the piribedil sustained-release tablets prepared in Examples 1-4 and the original formulation in different dissolution media are similar, while the release behaviors of Comparative Examples 2-5 and the original formulation in pH 1.0 hydrochloric acid medium are not similar.

[0112] In vivo bioequivalence study

[0113] The pharmacokinetic characteristics of a single oral administration of the pilot sample of Example 3 and a single oral administration of an imported drug (Batch No. 6049705) from ES LABORATOIRES SERVIER Co., Ltd. under the same conditions were investigated in healthy subjects under fasting conditions to evaluate the bioequivalence of the two preparations.

[0114]

[0115] It is proved that the piribedil sustained-release tablets provided by the present invention can achieve bioequivalence with the original research product in human experiments and can be a better substitute for the original research product.

[0116] Stability investigation

[0117] The piribedil sustained-release tablets prepared in Examples 1-4, the original research, and Comparative Examples 2-5 were placed in a stability test chamber at 40°C ± 2°C and RH 75% ± 5 for stability testing. Samples were taken at 0 and 6 months for testing, and the results are shown in Table 4.

[0118] Table 4: Results of accelerated test of Piribedil sustained-release tablets

[0119]

[0120]

[0121] In summary, the piribedil sustained-release tablets prepared in the embodiments of the present invention have the same in vitro dissolution behavior as the original research, are equivalent to the original research in the in vivo bioequivalence test, and have good quality stability, and can replace the original research product; the raw material cost is low, the preparation production process is simple, the process energy consumption is low, and it is easy to achieve large-scale industrial production.

[0122] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A piribedil sustained-release tablet, characterized in that: The piribedil sustained-release tablet comprises a core tablet and a coating layer, wherein the core tablet comprises the following components in weight percentage: 20%-30% piribedil, 65%-70% sustained-release material, 4%-8% binder, and 0.5%-2.0% lubricant; wherein the sustained-release material is talc; the coating layer comprises a water-soluble coating material and a water-insoluble coating material; the water-soluble coating material is HPMC coating powder; and the water-insoluble coating material is one or both of Eudragit RS30D aqueous dispersion and Eudragit RL30D aqueous dispersion; The D10 of the piribedil is 55 μm-90 μm, the D50 is 90 μm-125 μm, and the D90 is 125 μm-350 μm; The piribedil sustained-release tablets are prepared by the following method: S1, dissolving a binder in water to obtain a binder solution; spraying the binder solution onto the surface of a sustained-release material, wet granulating, drying, and sieving to obtain sustained-release granules; S2, mixing the piribedil raw material and the sustained-release granules uniformly, adding a lubricant, mixing uniformly, and tableting to obtain tablet cores; S3, adding a water-soluble coating material into water to obtain a water-soluble coating solution; adding the water-soluble coating solution into a water-insoluble coating material, mixing them evenly to obtain a mixed coating system; coating the tablet core with the mixed coating system to obtain piribedil sustained-release tablets.

2. The piribedil sustained-release tablet according to claim 1, wherein The binder is at least one of carboxymethyl cellulose, povidone, xanthan gum or gum arabic; and / or The lubricant is at least one of magnesium stearate, calcium stearate or sodium stearyl fumarate.

3. The piribedil sustained-release tablet according to claim 1, wherein The mass ratio of the water-soluble coating material to the water-insoluble coating material is 4:6-2:

8.

4. The piribedil sustained-release tablet according to claim 1, wherein The water-insoluble coating material is Eudragit RL30D aqueous dispersion.

5. The piribedil sustained-release tablet according to claim 1, wherein The coating layer accounts for 15%-30% of the mass of the tablet core.

6. A method for preparing the piribedil sustained-release tablet according to any one of claims 1 to 5, characterized in that: The steps include: S1, dissolving a binder in water to obtain a binder solution; spraying the binder solution onto the surface of a sustained-release material, wet granulating, drying, and sieving to obtain sustained-release granules; S2, mixing the piribedil raw material and the sustained-release granules uniformly, adding a lubricant, mixing uniformly, and tableting to obtain tablet cores; S3, adding a water-soluble coating material into water to obtain a water-soluble coating solution; adding the water-soluble coating solution into a water-insoluble coating material, mixing them evenly to obtain a mixed coating system; coating the tablet core with the mixed coating system to obtain piribedil sustained-release tablets.

7. The method for preparing the piribedil sustained-release tablets according to claim 6, wherein: In S1, the mass concentration of the binder solution is 5%-8%; and / or In S1, the spraying time is 2 min to 3 min, the stirring speed during the spraying process is 80 rpm to 150 rpm, and the chopping speed is 1000 rpm to 1800 rpm; and / or In S1, the particle size of the sustained-release granules is 40 mesh to 150 mesh; and / or In S2, the hardness of the tablet is 40N-80N; and / or In S3, the coating weight gain is 15%-30%.

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