Piribedil sustained release tablet and preparation method thereof

Abstract

The invention discloses a piribedil sustained-release tablet and a preparation method thereof, the sustained-release tablet comprises a tablet core containing piribedil or pharmaceutically acceptable salt thereof and a coating layer coated on the surface of the tablet core, the tablet core also contains povidone as an adhesive, talcum powder as a sustained-release material and magnesium stearate as a lubricant, the coating layer contains a water-soluble film-forming material, and the film-forming material is a water-soluble film-forming material. The water-soluble film-forming material is one or two of hydroxypropyl methyl cellulose and polyvinyl alcohol. The sustained release tablet provided by the invention adopts a relatively cheap coating material, so that the dissolution is consistent with that of a reference preparation, and the preparation process is simpler, easy to operate and suitable for industrial production.

Description

Technical Field

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

[0002] Parkinson's disease is a clinically common and refractory disease, a clinically common and refractory disorder that often causes movement disorders in the elderly. The motor dysfunction of Parkinson's disease stems from the loss of nigrostriatal dopaminergic neurons. Clinically, it is mainly manifested as resting tremor, bradykinesia, muscle rigidity, and abnormal posture and gait, which greatly affects the quality of life of patients.

[0003] Piribedil is a central dopamine receptor agonist that acts on postsynaptic D2 and D3 receptors. It improves the excitability of dopamine receptors, thereby increasing the level of receptor binding to dopamine, and restoring the balance between the acetylcholine and dopamine systems to exert an effect.

[0004] The original developed piribedil sustained-release tablet is a D2 and D3 dopamine receptor agonist developed by Servier Laboratories in France. Its chemical name is 2-(4-piperonyl-1-piperazinyl)pyrimidine, and its trade name is Trastal. It was first marketed in Europe in the 1960s. It has good tolerance, can improve the symptoms of Parkinson's disease, especially the improvement of tremors. Moreover, piribedil has obvious effects, few side effects, and is easy to control the drug dose.

[0005] According to the original research instructions, Trastal is a sugar-coated tablet. As is well known, the process of coating with sugar is rather cumbersome, requiring multiple steps such as coating the isolation layer, powder coat layer, sugar coat layer, and polishing, which takes a long time and requires relatively high experience from the operators. At the same time, the weight gain of the sugar coating fluctuates greatly, and it is prone to moisture absorption and color change, which limits its use in diabetic patients.

[0006] Film coating has the advantages of beautiful appearance, simple coating operation, relatively low requirements for the experience of operators, and high production efficiency. CN118743684 discloses a piribedil sustained-release tablet composition and a preparation method, which uses a water-soluble coating material and a water-insoluble coating material to replace the sugar coating. The water-soluble coating powder is HPMC-type Opadry coating powder, and the water-insoluble coating material is Eudragit aqueous dispersion. The HPMC-type Opadry coating powder comes from Colorcon and is a commonly used coating material for preparations, mainly acting as a pore-forming agent in the coating layer, while Eudragit plays a leading role. Its design mechanism is completely different from that of the present invention. Moreover, whether it is Opadry or Eudragit aqueous dispersion, their costs are higher than those of the coating materials of the present invention, and the coating preparation process requires two-step dispersion, with cumbersome operations.

[0007] The prior art has failed to obtain a method that can not only ensure consistency with the release curve of the original developed formulation, but also ensure low production costs and simple operation. Therefore, it is of great value to develop a formulation with high production efficiency, pharmaceutical consistency with the original developed formulation, and stability.

[0008] Due to the certain delayed release effect of the sugar coating of the original developed formulation, the inventors found during the research that only the coating with hydroxypropyl methylcellulose within a specific viscosity range or / and polyvinyl alcohol within a specific molecular weight range can make the prepared formulation exhibit a release behavior consistent with that of the original sugar coating. At the same time, when conducting stability tests on the self-made samples and the reference formulation, it was very unexpectedly found that the dissolution and release of the self-made tablets remained stable under the accelerated stability test conditions, while the release of the original developed formulation gradually became faster during storage.

[0009] In addition, the coating material in the present invention can be coated using conventional coating equipment, and has the advantages of small within-batch differences, short production cycle, low dependence on the proficiency of workers, good stability, etc., which is more conducive to industrial production. Summary of the Invention

[0010] The object of the present invention is to overcome the deficiencies of the prior art and provide a piribedil sustained-release tablet and its preparation method. The sustained-release tablet has a stable and controllable drug release rate, is consistent with the original developed formulation, and is conducive to industrial production.

[0011] The following implementation schemes are provided to achieve the object of the present invention.

[0012] In one implementation scheme, a piribedil sustained-release tablet of the present invention comprises a tablet core containing piribedil or its pharmaceutically acceptable salt and a coating layer coated on the surface of the tablet core, and the coating layer contains a water-soluble film-forming material.

[0013] In one implementation scheme, for the above-mentioned sustained-release tablet of the present invention, the tablet core further contains the binder povidone, the sustained-release material talc, and the lubricant magnesium stearate, and the coating layer further contains inorganic fillers and optional other additives.

[0014] Preferably, for the above-mentioned sustained-release tablet of the present invention, the water-soluble film-forming material is one or both of hydroxypropyl methylcellulose and polyvinyl alcohol.

[0015] Preferably, for the above-mentioned sustained-release tablet of the present invention, the viscosity of the hydroxypropyl methylcellulose is 15 - 100 mPa·s, preferably 60 - 100 mPa·s; the molecular weight of the polyvinyl alcohol is 20,000 - 100,000 daltons, preferably 40,000 - 100,000 daltons.

[0016] Preferably, for the above-mentioned sustained-release tablet of the present invention, the water-soluble film-forming material is hydroxypropyl methylcellulose and polyvinyl alcohol, and their weight ratio is 1:0 - 1:2.

[0017] Preferably, in the sustained-release tablet of the present invention described above, the inorganic filler in the coating layer is titanium dioxide or / and talcum powder.

[0018] Preferably, in the sustained-release tablet of the present invention described above, in the tablet core, the particle size of the talcum powder is ≤1200 mesh.

[0019] Preferably, in the sustained-release tablet of the present invention described above, the other additives in the coating layer include a plasticizer, a flavoring agent or other edible pigments.

[0020] Preferably, in the sustained-release tablet of the present invention described above, in the coating layer, the weight of the water-soluble film-forming material accounts for 25% to 70% of the total weight of the coating layer, preferably 30% to 70%.

[0021] Preferably, in the sustained-release tablet of the present invention described above, the coating weight gain is 20% to 45% of the weight of the tablet core, preferably 20 to 40%.

[0022] Preferably, in the sustained-release tablet of the present invention described above, per unit preparation of the tablet core, piribedil is 50 mg.

[0023] Preferably, in the sustained-release tablet of the present invention described above, the weight components of the tablet core are: 50 parts of piribedil, 130 parts of talcum powder, 20 parts of polyvinylpyrrolidone K30, and 4 parts of magnesium stearate.

[0024] Preferably, in the sustained-release tablet of the present invention described above, in a 0.1N HCl dissolution medium, the release amounts of the sustained-release tablet at 2 hours, 4 hours, 8 hours, and 16 hours should be 20% to 40%, 40% to 60%, 65% to 90%, and 90% to 110% respectively.

[0025] In another embodiment, a method for preparing a piribedil sustained-release tablet includes the following steps:

[0026] (1) Mix piribedil, a binder, and a sustained-release material into a uniform mixed powder;

[0027] (2) Add a wetting agent to the mixed powder in the previous step, granulate, dry, screen, and size the granules;

[0028] (3) After sizing, add a lubricant and mix evenly, then press tablets to obtain naked tablets;

[0029] (4) Add the naked tablets to a high-efficiency coating pan, spray a coating solution mainly composed of a water-soluble film-forming material, an inorganic filler, and optionally other additives and other coating materials for coating.

[0030] In the method for preparing the sustained-release tablet of the present invention described above, in step (4), the water-soluble film-forming material is one or two of hydroxypropyl methylcellulose and polyvinyl alcohol.

[0031] The preparation method of the sustained-release tablets of the present invention described above, wherein the viscosity of the hydroxypropyl methylcellulose is 15 to 100 mPa·s, preferably 60 to 100 mPa·s; the molecular weight of the polyvinyl alcohol is 20,000 to 100,000 Daltons, preferably 40,000 to 100,000 Daltons.

[0032] The preparation method of the sustained-release tablets of the present invention described above, wherein the water-soluble film-forming material is hydroxypropyl methylcellulose and polyvinyl alcohol, and their weight ratio is 1:0 to 1:2.

[0033] The preparation method of the sustained-release tablets of the present invention described above, wherein the weight of the water-soluble film-forming material accounts for 25% to 70% of the total weight of the coating layer, preferably 30% to 70%.

[0034] The preparation method of the sustained-release tablets of the present invention described above, wherein the coating weight gain is 20% to 45% of the weight of the tablet core, preferably 20% to 40%.

[0035] The preparation method of the sustained-release tablets of the present invention described above, wherein the coating inorganic filler is talc powder and silicon dioxide. Preferably, the weight ratio of talc powder to silicon dioxide is 3.5 to 5:1.

[0036] In the preparation method of the coating material for the sustained-release tablets of the present invention described above, other additives include plasticizers, flavoring agents or other edible pigments.

[0037] The in vitro dissolution determination method of the present invention:

[0038] In accordance with the second method (paddle method) of the dissolution and release determination method in the fourth part of the Chinese Pharmacopoeia 0931, the drug sample is placed in 1000 ml of a medium containing 0.1N HCl, and the paddle method is used at 100 rpm. 10 ml of the medium is taken at 1, 2, 4, 6, 8, 12, 16, and 24 hours respectively, and the drug release amount at each time point is determined by the ultraviolet method. The release degrees at 2h, 4h, 8h, and 16h are 20% to 40%, 40% to 60%, 65% to 90%, and 90% to 110% respectively.

[0039] Study on different coating film-forming agents

[0040] In the present invention, by studying the materials of different film-forming agents, hydroxypropyl methylcellulose, polyvinyl alcohol and a combination of the two materials are respectively selected as film-forming agents to prepare coating materials. Among them, the viscosity range of hydroxypropyl methylcellulose is 15 to 100 mPa·s, preferably 60 to 100 mPa·s; the molecular weight range of polyvinyl alcohol is 20,000 to 100,000 Daltons, and tablets are prepared.

[0041] The present invention uses the sustained-release piribedil tablets (trade name: Tasma) of Servier France as the reference preparation, and the products with different coating materials and different weight gains after coating as the test preparations. The batch-to-batch differences in in vitro dissolution of different coating materials are evaluated and the similarity of the dissolution curves is compared with the reference preparation. Further, products within a determined range are selected to conduct stability studies with the reference preparation. The research results show that the in vitro drug release behavior of the sustained-release tablets of the present invention is stable and controllable, and is consistent with the original developed preparation, with small within-batch differences. After stability studies, the products of the present invention maintain stability in in vitro dissolution during the stability investigation.

[0042] In a specific embodiment, for the sustained-release tablets of the present invention, the film-forming agent in the coating material is hypromellose with a viscosity of 60 mPa·s. The release degrees at 2 h, 4 h, 8 h, and 16 h in 0.1N hydrochloric acid medium are 20% - 40%, 40% - 60%, 65% - 90%, and 90% - 110% respectively, and the in vitro dissolution is consistent with that of the reference preparation.

[0043] In a specific embodiment, for the sustained-release tablets of the present invention, the film-forming agent of the coating material is polyvinyl alcohol: hypromellose at a ratio of 1:1, where the molecular weight of polyvinyl alcohol is 40,000 - 100,000 daltons, the viscosity of hypromellose is 60 mPa·s, and the coating weight gain is 25%. The release degrees at 2 h, 4 h, 8 h, and 16 h in 0.1N hydrochloric acid medium are 20% - 40%, 40% - 60%, 65% - 90%, and 90% - 110% respectively, and the in vitro dissolution is consistent with that of the reference preparation.

[0044] In a specific embodiment, for the sustained-release tablets of the present invention, the film-forming agent of the coating material is polyvinyl alcohol: hypromellose at a ratio of 2:1, where the molecular weight of polyvinyl alcohol is 40,000 - 100,000 daltons, the viscosity of hypromellose is 60 mPa·s, and the coating weight gain is 25%. The release degrees at 2 h, 4 h, 8 h, and 16 h in 0.1N hydrochloric acid medium are 20% - 40%, 40% - 60%, 65% - 90%, and 90% - 110% respectively, and the in vitro dissolution is consistent with that of the reference preparation.

[0045] In a specific embodiment, for the sustained-release tablets of the present invention, the film-forming agent of the coating material is hypromellose with a viscosity of 60 mPa·s and the coating weight gain is 35%. The prepared samples and the reference preparation are packaged in the same way and placed under the conditions of 40°C and 75% RH for investigation. The dissolution of the preparation of the present invention remains stable under accelerated conditions, while the dissolution of the reference preparation changes significantly.

[0046] In another embodiment, for the sustained-release tablets of the present invention, the film-forming agent of the coating material is polyvinyl alcohol: hydroxypropyl methylcellulose at a ratio of 1:1, wherein the molecular weight of polyvinyl alcohol is 40,000 - 100,000 Daltons, the viscosity of hydroxypropyl methylcellulose is 60 mPa·s, and the coating weight gain is 20%. The prepared samples and the reference preparation were packaged in the same way and placed at 40°C and 75% RH for investigation respectively. The dissolution of the preparation of the present invention remained stable under accelerated conditions, while the dissolution of the reference preparation changed significantly.

[0047] Technical effects: The sustained-release tablets of the present invention use relatively inexpensive coating materials and can be coated with conventional coating equipment. They have the advantages of small within-batch differences, short production cycles, low dependence on the proficiency of workers, and good stability. They can not only achieve the same dissolution as the reference preparation, but also have a simpler preparation process, are easy to operate, and are suitable for industrial production. Detailed implementation manners

[0048] The following examples are for a more detailed description of the present invention. However, the following examples are provided only to help further understand the present invention and are not intended to limit the present invention. Those skilled in the art should understand that equivalent substitutions or corresponding improvements made to the content of the present invention still fall within the protection scope of the present invention.

[0049] In the following examples, regarding the determination of drug dissolution:

[0050] The dissolution determination method is the second method (paddle method) in the fourth part of the Chinese Pharmacopoeia 0931 Dissolution and Release Determination Method. The drug sample is placed in 1000 ml of medium containing 0.1N HCl, and the paddle method is used at 100 rpm. 10 ml of the medium is taken at 1, 2, 4, 6, 8, 12, 16, and 24 hours respectively, and the ultraviolet method is used to determine the drug release amount at each time point.

[0051] Examples 1 - 3 Pramipexole Sustained-Release Tablets

[0052] The prescription of the pramipexole sustained-release tablets is shown in Table 1 below, which represents the composition of a laboratory-scale batch (1000 tablets) containing pramipexole and various excipients; the composition of the coating powder is shown in Table 1, and the tablets are coated with coating powders containing film-forming materials of hydroxypropyl methylcellulose with different viscosities, and the coating weight gain is 35% for all.

[0053] Table 1. Prescription of Pramipexole Sustained-Release Tablets and Composition of Coating Powder in Examples 1 - 3

[0054]

[0055] Preparation method:

[0056] (1) Mix the active ingredient pramipexole, the binder povidone, and the sustained-release material talc into a uniform mixture;

[0057] (2) Add a wetting agent to the powder of the mixture in step (1), granulate, and dry until the moisture content meets the requirements;

[0058] (3) Screen and size the granules, add the lubricant magnesium stearate, mix evenly, determine the granule content, and use a suitable punch die to press tablets;

[0059] (4) Using a high - efficiency coating pan, dissolve hypromellose, talc, titanium dioxide, and edible pigment in water, stir evenly to obtain a coating solution with a solid content of 9%, and perform atomized coating.

[0060] Examples 4 - 6 Pramipexole Sustained - Release Tablets

[0061] The prescriptions for the pramipexole sustained - release tablets and the coating powder are shown in Table 2, which represents the compositions of laboratory - scale batches (1000 tablets) containing pramipexole and various excipients. In Example 4, the molecular weight of polyvinyl alcohol is 40,000 - 100,000 daltons, the ratio of the amount of hypromellose (viscosity 60 mPa·s) to polyvinyl alcohol is 1:1, and the total amount accounts for 50% of the weight of the coating powder, and the coating weight gain accounts for 25% of the weight of the tablet core; in Example 5, the molecular weight of polyvinyl alcohol is 20,000 - 50,000 daltons, the ratio of the amount of hypromellose to polyvinyl alcohol is 1:1, and the total amount accounts for 50% of the weight of the coating powder, and the coating weight gain accounts for 25% of the weight of the tablet core; in Example 6, the molecular weight of polyvinyl alcohol is 40,000 - 100,000 daltons, the ratio of the amount of hypromellose (viscosity 60 mPa·s) to polyvinyl alcohol is approximately 1:2, and the coating weight gain accounts for 25% of the weight of the tablet core.

[0062] Table 2. Prescriptions for the pramipexole sustained - release tablets and the coating powder in Examples 4 - 6

[0063]

[0064] The preparations of Examples 4 - 6 refer to the preparation method of Example 1 to prepare the tablet core and coating, and the compositions of the coating solutions are different.

[0065] Examples 7 - 9 Pramipexole Sustained - Release Tablets

[0066] The prescriptions for the pramipexole sustained - release tablets and the coating powder are shown in Table 3, which represents the compositions of laboratory - scale batches (1000 tablets) containing pramipexole and various excipients. In Examples 7 - 9, the film - forming materials are polyvinyl alcohol and hypromellose, and the total amount of the film - forming agent accounts for 25% - 70% of the weight of the coating powder, and the coating weight gain accounts for 25% of the weight of the tablet core.

[0067] Table 3. Prescriptions for the pramipexole sustained - release tablets and the coating powder in Examples 7 - 9

[0068]

[0069] The tablets cores and coatings of Examples 7 to 9 were prepared with reference to the preparation method of Example 1, and the coating solution compositions were different.

[0070] Piribedil Sustained Release Tablets of Examples 10 to 13

[0071] The prescriptions of piribedil sustained release tablets and coating powders are shown in Table 4, which shows the compositions of laboratory-scale batches (1000 tablets) containing piribedil and various excipients. Among Examples 10 to 12, the ratio of polyvinyl alcohol to hypromellose in the film-forming material is 1:1, the molecular weight of polyvinyl alcohol is 40,000 - 100,000 daltons, the viscosity of hypromellose is 60 mPa·s, and the coating weight gain is 20% - 45%; the coating material of Example 13 is the same as that of Example 2, and the coating weight gain is 45%.

[0072] Table 4 Prescriptions of Piribedil Sustained Release Tablets and Coating Powders of Examples 10 to 12

[0073]

[0074]

[0075] The tablets cores and coatings of Examples 10 to 13 were prepared with reference to the preparation method of Example 1, and the coating solution compositions were different.

[0076] Piribedil Sustained Release Tablets of Comparative Examples 1 to 6

[0077] The prescriptions of piribedil sustained release tablets and coating powders of Comparative Example 1 are shown in Table 5, those of Comparative Examples 2 - 4 are shown in Table 6, and those of Comparative Examples 5 and 6 are shown in Tables 7 and 8 respectively. The tables show the compositions of laboratory-scale batches (1000 tablets) containing piribedil and various excipients. Among them, the sustained release tablet core of Comparative Example 1 uses sugar coating, and the coating weight gain is 58%; Comparative Example 2 uses hypromellose with a viscosity of 5 mPa·s as the film-forming material for coating, and the weight gain is 40%; Comparative Example 3 uses a combination of hypromellose with a viscosity of 5 mPa·s and polyvinyl alcohol (40,000 - 100,000 daltons) at a ratio of 1:1 as the film-forming material for coating; Comparative Example 4 uses a combination of hypromellose with a viscosity of 60 mPa·s and polyvinyl alcohol (150,000 daltons) at a ratio of 1:1 as the film-forming material for coating; Comparative Example 5 uses a combination of hypromellose with a viscosity of 60 mPa·s and polyvinyl alcohol (40,000 - 100,000 daltons) at a ratio of 1:3 as the film-forming material for coating; Comparative Example 6 formulates the coating solution according to the ratio of HPMC-type Opadry: Eudragit RS30D aqueous dispersion of 3:7, and the coating weight gain is 25%.

[0078] Table 5 Prescription and Coating of Piribedil Sustained Release Tablets of Comparative Example 1

[0079]

[0080]

[0081] Table 6. Formulations of piribedil sustained-release tablets and coating powder for Comparative Examples 2-4

[0082]

[0083] Table 7. Formulations of piribedil sustained-release tablets and coating powder for Comparative Example 5

[0084]

[0085] Preparation method of the sustained-release tablets of Comparative Example 1:

[0086] (1) The preparation method of the tablet core refers to Example 1

[0087] (2) Coating:

[0088] Apply the isolating layer, powder coat layer and sugar coat layer.

[0089] The preparation of the sustained-release tablets of Comparative Examples 2-5 refers to the preparation method of Example 1.

[0090] Table 8. Formulations of piribedil sustained-release tablets and coating powder for Comparative Example 6

[0091]

[0092] Preparation method:

[0093] (1) Mix the active ingredient piribedil, the binder povidone and the sustained-release material talc into a homogeneous mixture;

[0094] (2) Add the wetting agent to the powder of the mixture in the previous step, granulate, dry until the moisture content meets the requirements; screen, size, add the lubricant magnesium stearate and mix evenly, measure the particle content, and use a suitable punch die to press tablets;

[0095] (3) Prepare a 13% HPMC type Opadry coating powder solution with 100 g of purified water, and then slowly add it to 116.7 g of Eudragit RL30D aqueous dispersion (solid content 30%, dry weight 35 g), and continuously stir for 30 min to obtain a mixed coating system; Take 1000 tablet cores for coating, and the coating weight gain is 25%.

[0096] In vitro release curve determination

[0097] The sustained-release tablets of Examples 1 to 12, the sustained-release tablets of Comparative Examples 2 to 6, and the original developed preparation, Trastal (used as the reference preparation), were respectively subjected to dissolution tests. The dissolution determination method was the second method (paddle method) in the Determination of Dissolution and Release Rate in the Fourth Part of the Chinese Pharmacopoeia. The drug sample was placed in a medium containing 1000 ml of 0.1N HCl, and the paddle method was used at 100 rpm. 10 ml of the medium was taken at 1, 2, 4, 6, 8, 12, 16, and 24 hours respectively, and the ultraviolet method was used for determination. The results are shown in Tables 9 to 13 respectively.

[0098] Table 9. Release rate and f2 similarity factor of the sustained-release tablets of Examples 1 to 3 and Comparative Example 2

[0099] Time Example 1 Example 2 Example 3 Comparative Example 2 Reference Preparation 1 20 10 7 29 13 2 37 32 25 47 28 4 58 51 44 65 50 6 71 62 58 74 64 8 82 77 69 88 75 12 94 87 82 98 89 16 97 98 93 101 97 24 97 97 99 100 99 f2 similarity factor 58 79 63 42 /

[0100] The data in Table 9 above show that when the coating material prepared with hydroxypropyl methylcellulose with a viscosity of 15 to 100 mPa·s was used for coating, the release rate of the resulting piribedil sustained-release tablet samples was tested, and the release rate was similar to that of the reference preparation, and the f2 similarity factor was > 50; while in Comparative Example 2, after coating with a coating powder containing hydroxypropyl methylcellulose with a viscosity of 5 mPa·s as the film-forming material, the dissolution of the prepared sample was relatively fast and not similar to the reference preparation.

[0101] Table 10. Release rate and f2 similarity factor of the sustained-release tablets of Examples 4 to 5 and Comparative Example 4

[0102] Time / h Example 4 Example 5 Comparative Example 4 Reference Preparation 1 11 16 6 13 2 29 33 18 28 4 50 53 41 50 6 61 67 56 64 8 74 79 67 75 12 88 90 80 89 16 98 96 92 97 24 98 99 95 99 f2 similarity factor 86 73 54 /

[0103] The dissolution results of the samples of Examples 4 to 5 show that within the range of 20,000 to 100,000 daltons of the molecular weight of polyvinyl alcohol, the dissolution of the prepared sustained-release tablets was consistent with that of the original developed preparation, and the f2 value was > 50; in Comparative Example 4, when polyvinyl alcohol with a molecular weight of 150,000 was used for coating, the release rate at 2 h was lower than the quality standard range, and the release rate of the product was unqualified.

[0104] Table 11. Release rate and f2 similarity factor of the sustained-release tablets of Examples 6 to 9 and Comparative Example 5

[0105] Time / h Example 6 Example 7 Example 8 Example 9 Comparative Example 5 Reference Preparation 1 10 7 20 21 6 13 2 27 26 37 38 18 28 4 47 43 57 57 36 50 6 60 58 69 70 53 64 8 72 69 82 81 68 75 12 85 80 93 94 80 89 16 92 91 95 96 88 97 24 96 94 95 99 92 99 f2 similarity factor 73 78 58 58 51 /

[0106] The dissolution results in Table 11 show that when the dosage ratio of hydroxypropyl methylcellulose to polyvinyl alcohol is within the range of 1:0 to 1:2, and the total dosage of the two accounts for 25% - 70% of the coating material, the dissolution of the preparation is consistent with that of the original developed preparation (reference preparation), and the f2 value is > 50; Comparative Example 5 shows that when the dosage of hydroxypropyl cellulose and polyvinyl alcohol is 1:3 and the coating weight gain is 25%, the release rates at 2 h and 4 h of the tablets in the pH 1.0 medium exceed the quality standard range and do not meet the product quality requirements.

[0107] Table 12. Release rate and f2 similarity factor of the sustained-release tablets of Examples 10 to 13 and Comparative Example 3

[0108] Time / h Example 10 Example 11 Example 12 Example 13 Reference Preparation 1 17 12 9 8 13 2 36 33 24 28 28 4 57 53 45 49 50 6 70 65 60 62 64 8 80 74 69 73 75 12 95 91 81 84 89 16 101 96 93 95 97 24 101 100 96 99 99 f2 similarity factor 61 78 67 78 /

[0109] Table 13. Dissolution rate and f2 similarity factor of sustained-release tablets of Example 11 and Comparative Examples 3 and 6

[0110] Time / h Example 11 Comparative Example 3 Comparative Example 6 1 12 22 19 2 33 44 38 4 53 63 61 6 65 70 77 8 74 85 88 12 91 96 96 16 96 98 100 24 100 98 100 f2 similarity factor 78 47 48

[0111] The dissolution results in Table 12 and Table 13 show that when the coating weight gain accounts for 20 - 45% of the tablet core, the dissolution of the sustained-release tablets is consistent with that of the reference preparation; however, the release of the sustained-release tablets in Comparative Example 3 is still too fast after using a coating powder with a medium-low viscosity hydroxypropyl methylcellulose and polyvinyl alcohol in a 1:1 ratio, and the f2 similarity factor < 50; in Comparative Example 6, the HPMC type Opadry: Eudragit RS30D aqueous dispersion in a ratio of 3:7 is used as the coating material, and the coating weight gain is 25%. The dissolution rate of the tablets in the pH 1.0 medium at 4 h is 61%, exceeding the requirement range of 40% - 60% of the standard, and the evaluation using the f2 similarity factor is 48 < 50, which is not similar to the reference preparation.

[0112] Coating time comparison

[0113] Compare the time taken for the coating processes of Examples 2, 10, and 12 with that of Comparative Example 1. The results are shown in Table 14.

[0114] Table 14. Coating time comparison of Examples 2, 10, 12 and Comparative Examples 1 and 6

[0115] Time Example 10 Example 2 Example 12 Comparative Example 1 Comparative Example 6 Duration of coating process 6 hours 10 hours 13 hours 21 hours 16h

[0116] The results in Table 14 show that using the coating materials of the present invention, the coating time for Examples 2, 10, and 12 is 6 - 13 hours, which is significantly shorter than the 21-hour coating time of Comparative Example 1, and significantly improves the commercial production efficiency.

[0117] Coating weight gain uniformity comparison

[0118] Take 10 coated tablets from the sustained-release tablet samples prepared in Examples 2 and 10 and the sustained-release tablet sample of Comparative Example 1 respectively, measure their coating weight gain, and calculate their RSD%. The results are shown in Table 15 below.

[0119] Table 15. Coating weight gain uniformity comparison of Examples 2 and 10 and Comparative Example 1

[0120]

[0121] The results in Table 15 show that using the film coating powder combination of the present invention for coating, the coating uniformity of the tablets is significantly improved compared with that of sugar coating.

[0122] Stability study

[0123] The present invention aims to invent a piribedil sustained-release tablet suitable for commercial production, which can improve the within-batch uniformity and ensure the product stability. For this purpose, the piribedil sustained-release tablets of the present invention and the original developed preparation (reference preparation) were subjected to an accelerated stability test. The piribedil sustained-release tablets of Example 2 and Example 10 and the reference preparation were packaged in the same way and placed at 40°C and 75% RH for investigation. Samples were taken at 3 months and 6 months respectively to determine the dissolution rate. The results are shown in Table 16.

[0124] Table 16. Comparison of dissolution rates of the sustained-release tablets of Example 2 and 10 and the reference preparation under accelerated conditions

[0125]

[0126]

[0127] The results in Table 16 show that according to the quality standard requirements, the dissolution behavior of the piribedil sustained-release tablets of the present invention in 0.1N hydrochloric acid medium has release rates of 20% - 40%, 40% - 60%, 65% - 90%, and 90% - 110% at 2h, 4h, 8h, and 16h respectively. However, the dissolution of the reference preparation exceeded the limit at 4h after 3 months of acceleration. As the investigation time extended, the dissolution of the reference preparation gradually became faster; while the dissolution rate of the self-made product of the present invention remained stable during the accelerated test.

Claims

1. A piribedil sustained-release tablet, comprising a tablet core containing piribedil or a pharmaceutically acceptable salt thereof and a coating layer coated on the surface of the tablet core, wherein the coating layer contains a water-soluble film-forming material.

2. The sustained-release tablet according to claim 1, wherein the tablet core further comprises a binder, polyvidone, a sustained-release material, talc, and a lubricant, magnesium stearate, and the coating layer further comprises an inorganic filler and optionally other additives.

3. The sustained-release tablet according to claim 1, wherein the water-soluble film-forming material is one or both of hydroxypropylmethylcellulose and polyvinyl alcohol.

4. The sustained-release tablet according to claim 3, wherein the viscosity of the hydroxypropyl methylcellulose is 15 to 100 mPa.s, preferably 60 to 100 mPa.s; and the molecular weight of the polyvinyl alcohol is 20,000 to 100,000 Daltons, preferably 40,000 to 100,000 Daltons.

5. The sustained-release tablet according to claim 3, wherein the water-soluble film-forming material is hydroxypropyl methylcellulose and polyvinyl alcohol, and the weight ratio thereof is 1:0 to 1:

2.

6. The sustained-release tablet according to claim 2, wherein the inorganic filler in the coating layer is titanium dioxide and / or talc.

7. The sustained-release tablet according to claim 2, wherein the particle size of the talc in the tablet core is ≤1200 mesh.

8. The sustained-release tablet as claimed in claim 2, wherein other additives in the coating layer include plasticizers, flavoring agents or other edible pigments.

9. The sustained-release tablet according to claim 1, wherein the weight of the water-soluble film-forming material in the coating layer accounts for 25% to 70%, preferably 30% to 70%, of the total weight of the coating layer.

10. The sustained-release tablet according to any one of claims 1 to 9, wherein the coating weight gain is 20% to 45%, preferably 20 to 40%, of the weight of the tablet core.

11. The sustained-release tablet according to claim 10, wherein the content of piribedil in the tablet core is 50 mg per unit of preparation.

12. The sustained-release tablet according to claim 11, wherein the weight components of the tablet core are: 50 parts of piribedil, 130 parts of talc, 20 parts of povidone K30 and 4 parts of magnesium stearate.

13. The sustained-release tablet according to any one of claims 1 to 9, wherein in a 0.1N HCl dissolution medium, the release amount of the sustained-release tablet in 2 hours, 4 hours, 8 hours, and 16 hours is 20% to 40%, 40% to 60%, 65% to 90%, and 90% to 110%, respectively.

14. A method for preparing the piribedil sustained-release tablets according to claims 1-13, comprising the following steps: (1) mixing piribedil, a binder, and a sustained-release material into a uniform mixed powder; (2) adding a wetting agent to the mixed powder from the previous step, granulating, drying, sieving, and granulating; (3) adding a lubricant to the pellets and mixing them evenly, and pressing them into tablets to obtain bare tablets; (4) Add the bare chips to a high-efficiency coating pan and spray a coating solution mainly composed of a water-soluble film-forming material, an inorganic filler and optionally other additives to coat the chips.

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