Piribedil sustained release tablet and preparation method thereof

Abstract

The invention relates to a piribedil sustained-release tablet, the sustained-release tablet comprises piribedil, talcum powder, a sustained-release material, an adhesive and a lubricant, the sustained-release material is hydroxypropyl methylcellulose, and the dissolution similar factor f2 of the sustained-release tablet and an original reference preparation Tesuda # imgabs0 # is greater than or equal to 50. According to the piribedil sustained-release tablet disclosed by the invention, on the basis that a sugar-coating layer is not coated, by optimizing a prescription and adding a hydroxypropyl methylcellulose sustained-release material, the technical effect of in-vivo bioequivalence with that of an original reference preparation Tesuda # imgabs1 # is obtained.

Description

Technical Field

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

[0002] Piribedil is a central dopamine receptor agonist that acts on postsynaptic D2 and D3 receptors, increasing the excitability of dopamine receptors, thereby increasing the level of receptor-dopamine binding, restoring the balance between acetylcholine and dopamine systems and exerting its effect. As a D2 and D3 receptor agonist, piribedil has good tolerance and can improve Parkinson's disease symptoms, especially tremor. Piribedil also has the advantages of obvious effects, few side effects, and easy control of drug dosage.

[0003] The original product of Piribedil sustained-release tablets currently on the domestic market is called It was developed and marketed by the French company Servier and approved for import and marketing in 2014. The sustained-release tablet core is coated with sugar. The sustained-release skeleton material of the tablet core is talcum powder. Although it is cheap, the skeleton system also shows good controlled-release effect in in vitro dissolution test. However, the strength of the skeleton system is limited. When it is subjected to strong gastrointestinal peristalsis or food squeezing in the body, the risk of sudden release increases. In addition, the sustained-release tablet core has a thicker sugar coating, which increases the weight by about 60%. If the gastrointestinal peristalsis effect is weak after the tablet is taken into the body, the excessively thick sugar coating will delay or even block the release of the tablet core in the body. The original product adopts the above-mentioned formulation composition design, which causes high variability in the human body, which in turn brings fluctuations in blood drug concentration and affects the efficacy of the drug.

[0004] All piribedil sustained-release tablets reported in existing literature need to be coated to achieve release characteristics similar to the original sugar-coated tablets. However, the design of the coating layer requires the use of a coating device during the production process, which increases production costs. In addition, improper selection of coating materials and thickness will still lead to delayed release of coated sustained-release tablets in the body. Report on in vivo bioequivalence of piribedil sustained-release tablets without coating layer. Summary of the invention

[0005] To solve the above technical problems, the present invention includes the following aspects:

[0006] The first aspect of the present invention provides a piribedil sustained-release tablet, the sustained-release tablet comprising piribedil, talcum powder, a sustained-release material, a binder and a lubricant, the sustained-release material being hypromellose, the sustained-release tablet being different from the original reference preparation The dissolution similarity factor f2 is greater than or equal to 50.

[0007] Preferably, the sustained-release tablet does not contain any coating layer. More preferably, the sustained-release tablet does not contain a sugar coating layer.

[0008] Preferably, the weight percentage of piribedil in the sustained-release tablet is 10-20%. More preferably, the weight percentage of piribedil in the sustained-release tablet is 15-20%. Further preferably, the weight percentage of piribedil in the sustained-release tablet is 16-18%. Further preferably, the weight percentage of piribedil in the sustained-release tablet is 16.7%.

[0009] Preferably, the particle size range of the talcum powder is as follows: 90 <100 μm, D 50 <60μm, D 10 <30 μm. More preferably, the particle size range of the talc is as follows: D 90 <90μm, D 50 <50μm, D 10 <20 μm. Further preferably, the particle size range of the talc powder is as follows: D 90 <75μm, D 50 <45μm, D 10 <15μm.

[0010] Preferably, the weight percentage of the talc in the sustained-release tablet is 40-70%. More preferably, the weight percentage of the talc in the sustained-release tablet is 50-60%. Further preferably, the weight percentage of the talc in the sustained-release tablet is 50-55%. Further preferably, the weight percentage of the talc in the sustained-release tablet is 54%.

[0011] Preferably, the hypromellose is selected from one or more of hypromellose E4M and hypromellose K4M. Preferably, the hypromellose is hypromellose E4M or hypromellose K4M. Further preferably, the hypromellose is hypromellose E4M.

[0012] Preferably, the weight percentage of the hypromellose in the sustained-release tablet is 5-30%. More preferably, the weight percentage of the hypromellose in the sustained-release tablet is 10-20%. Further preferably, the weight percentage of the hypromellose in the sustained-release tablet is 15-20%. Further preferably, the weight percentage of the hypromellose in the sustained-release tablet is 18%.

[0013] Preferably, the weight ratio of talc to hypromellose is 1:1-10:1. More preferably, the weight ratio of talc to hypromellose is 2:1-8:1. Further preferably, the weight ratio of talc to hypromellose is 2:1-6:1. Further preferably, the weight ratio of talc to hypromellose is 2:1-4:1, for example 2:1, 2.5:1, 3:1, 3.5:1 and 4:1.

[0014] Preferably, the binder is selected from one or more of povidone, low-substituted hydroxypropyl cellulose, and starch. More preferably, the binder is selected from one or more of povidone and low-substituted hydroxypropyl cellulose. Further preferably, the binder is povidone. Further preferably, the binder is povidone K30.

[0015] Preferably, the weight percentage of the adhesive in the sustained-release tablet is 5-20%. More preferably, the weight percentage of the adhesive in the sustained-release tablet is 10-15%. Further preferably, the weight percentage of the adhesive in the sustained-release tablet is 10-12%. Further preferably, the weight percentage of the adhesive in the sustained-release tablet is 10%.

[0016] Preferably, the lubricant is selected from one or more of magnesium stearate, calcium stearate, zinc stearate, and stearic acid. More preferably, the lubricant is selected from one or more of magnesium stearate and calcium stearate. Further preferably, the lubricant is magnesium stearate.

[0017] Preferably, the weight percentage of the lubricant in the sustained-release tablet is 0.5-5%. More preferably, the weight percentage of the lubricant in the sustained-release tablet is 0.8-3%. Further preferably, the weight percentage of the lubricant in the sustained-release tablet is 1-2%. Further preferably, the weight percentage of the lubricant in the sustained-release tablet is 1-1.5%. Further preferably, the weight percentage of the lubricant in the sustained-release tablet is 1.3%.

[0018] Preferably, the piribedil is micronized. More preferably, the particle size D of the piribedil is 90 Less than 50 μm. Further preferably, the particle size D of the piribedil 90 More preferably, the particle size D of the piribedil is 90 Less than 10μm.

[0019] Preferably, the sustained-release tablet comprises 50 mg of micronized piribedil, 150 mg of talc, 60 mg of hypromellose K4M, 36 mg of povidone K30 and 4 mg of magnesium stearate.

[0020] Preferably, the sustained-release tablet comprises 50 mg of micronized piribedil, 165 mg of talc, 45 mg of hypromellose K4M, 36 mg of povidone K30 and 4 mg of magnesium stearate.

[0021] Preferably, the sustained-release tablet comprises 50 mg of micronized piribedil, 180 mg of talc, 30 mg of hypromellose K4M, 36 mg of povidone K30 and 4 mg of magnesium stearate.

[0022] Preferably, the sustained-release tablet comprises 50 mg of micronized piribedil, 162 mg of talc, 54 mg of hypromellose K4M, 30 mg of povidone K30 and 4 mg of magnesium stearate.

[0023] Preferably, the sustained-release tablet comprises 50 mg of micronized piribedil, 150 mg of talc, 60 mg of hypromellose E4M, 36 mg of povidone K30 and 4 mg of magnesium stearate.

[0024] Preferably, the sustained-release tablet is different from the original reference preparation The dissolution similarity factor f2 is greater than or equal to 55. More preferably, the sustained-release tablet is similar to the original reference preparation. The dissolution similarity factor f2 is greater than or equal to 60. Further preferably, the sustained-release tablet is similar to the original reference preparation The dissolution similarity factor f2 is greater than or equal to 65. Further preferably, the sustained-release tablet is similar to the original reference preparation The dissolution similarity factor f2 is greater than or equal to 70. Further preferably, the sustained-release tablet is similar to the original reference preparation The dissolution similarity factor f2 is greater than or equal to 75.

[0025] Preferably, the sustained-release tablet is Bioequivalent in vivo.

[0026] Preferably, the sustained-release tablet is The specifications are all 50mg.

[0027] The second aspect of the present invention provides a method for preparing the above-mentioned piribedil sustained-release tablets, the preparation method comprising the following steps:

[0028] (1) dissolving a prescribed amount of adhesive in purified water to prepare an adhesive solution;

[0029] (2) weighing the prescribed amount of piribedil, talc and sustained-release material, and using the binder solution obtained in step (1) to prepare granules through a fluidized bed process;

[0030] (3) The particles obtained in step (2) are sized by a pulverizer, and the sized particles are mixed with a prescribed amount of lubricant in a mixer to obtain a total mixture;

[0031] (4) tabletting the total mixture obtained in step (3) using a high-speed rotary tablet press to obtain the product.

[0032] Preferably, the weight ratio of the binder to purified water in step (1) is 1:4.

[0033] Preferably, during the liquid spraying process of the fluidized bed granulation in step (2), the air inlet temperature of the fluidized bed is controlled at 38-48°C.

[0034] Preferably, after the liquid spraying of the fluidized bed granulation in step (2) is completed, the inlet air temperature is increased to dry the granules, heated to a material temperature of 40-60° C., and maintained for 10-20 minutes until the drying loss is no more than 2.0%. More preferably, after the liquid spraying of the fluidized bed granulation in step (2) is completed, the inlet air temperature is increased to dry the granules, heated to a material temperature of 50° C., and maintained for 10-20 minutes until the drying loss is no more than 2.0%.

[0035] Preferably, the mixing time in step (3) is 1-10 minutes. More preferably, the mixing time in step (3) is 3-8 minutes. Further preferably, the mixing time in step (3) is 5 minutes.

[0036] Preferably, the size of the pulverizing screen of the pulverizer in step (3) is 1 mm.

[0037] Preferably, in step (4), an 8 mm shallow concave punch is selected for tableting.

[0038] Preferably, the core hardness of the sustained-release tablet obtained in step (4) is controlled at 50-100N, and the friability does not exceed 1.0%.

[0039] The third aspect of the present invention provides use of the above-mentioned piribedil sustained-release tablets in the preparation of a drug for treating Parkinson's disease.

[0040] The fourth aspect of the present invention provides an in vitro dissolution test method for the above-mentioned piribedil sustained-release tablets, and the test method is the dissolution method 7 apparatus (reciprocating cylinder method) specified in the General Rules 0931 of Part IV of the 2020 edition of the Chinese Pharmacopoeia.

[0041] Preferably, in the test method, the reciprocating frequency of the reciprocating cylinder is 20 dpm, the release medium is 250 ml of 0.1N hydrochloric acid solution, and the dissolution medium temperature is 37°C±0.5°C.

[0042] Preferably, the test method comprises the following steps: taking samples at 0.5, 1, 2, 3, 4, 6 and 8 hours, respectively, sampling 5 ml of the solution each time, filtering with a 0.45 μm filter membrane, and immediately adding 5 ml of the above-mentioned medium; taking the subsequent filtrate as the test solution, and detecting the cumulative dissolution at each time point.

[0043] Preferably, the release amounts of the piribedil sustained-release tablets in the above test method at 0.5 hours, 2 hours, 4 hours and 8 hours should be ≤25%, 40-60%, 75-95% and ≥90%, respectively.

[0044] The fifth aspect of the present invention provides an application of a sustained-release material composition in regulating the release rate of a piribedil sustained-release tablet, wherein the sustained-release material composition comprises talcum powder and hypromellose, and the piribedil sustained-release tablet is different from the original reference preparation. The dissolution similarity factor f2 is greater than or equal to 50.

[0045] Preferably, the sustained-release tablet does not contain any coating layer. More preferably, the sustained-release tablet does not contain a sugar coating layer.

[0046] Preferably, the hypromellose is selected from one or more of hypromellose E4M and hypromellose K4M. Preferably, the hypromellose is hypromellose E4M or hypromellose K4M. Further preferably, the hypromellose is hypromellose E4M.

[0047] Preferably, the weight ratio of talc to hypromellose is 1:1-10:1. More preferably, the weight ratio of talc to hypromellose is 2:1-8:1. Further preferably, the weight ratio of talc to hypromellose is 2:1-6:1. Further preferably, the weight ratio of talc to hypromellose is 2:1-4:1, for example 2:1, 2.5:1, 3:1, 3.5:1 and 4:1.

[0048] Preferably, the sustained-release tablet is different from the original reference preparation The dissolution similarity factor f2 is greater than or equal to 55. More preferably, the sustained-release tablet is similar to the original reference preparation. The dissolution similarity factor f2 is greater than or equal to 60. Further preferably, the sustained-release tablet is similar to the original reference preparation The dissolution similarity factor f2 is greater than or equal to 65. Further preferably, the sustained-release tablet is similar to the original reference preparation The dissolution similarity factor f2 is greater than or equal to 70. Further preferably, the sustained-release tablet is similar to the original reference preparation The dissolution similarity factor f2 is greater than or equal to 75.

[0049] The technical effects produced by the present invention are:

[0050] 1. The piribedil sustained-release tablets of the present invention are not coated with a sugar coating layer, but are optimized in prescription and added with a hydroxypropyl methylcellulose sustained-release material (such as hydroxypropyl methylcellulose E4M, hydroxypropyl methylcellulose K4M, etc.), thereby improving the problem of large in vivo release variation of the original product after administration, and obtaining a similar product to the original reference preparation. In vivo bioequivalence of piribedil extended-release tablets.

[0051] 2. The piribedil sustained-release tablets of the present invention adopt a fluidized bed granulation process, and the production process is simple and controllable, which can improve the fluidity and compressibility of the material and ensure the uniformity of the distribution of the active ingredient.

[0052] 3. The inventors found in the process of developing the piribedil sustained-release tablets that the dissolution determination method in the original product import registration standard has limited ability to distinguish the release behavior of the prescription. The present invention provides a new dissolution method, which has a strong ability to distinguish the release of the prescription, and can be used not only for the in vitro dissolution test and in vivo bioequivalence test of the sustained-release tablets of the present invention, but also for batch-to-batch quality control and stability assessment. DETAILED DESCRIPTION

[0053] The particle size D of the micronized piribedil used in each formulation of the following test examples of the present invention is 90 All are less than 10μm.

[0054] Test Example 1: In vitro dissolution and in vivo bioequivalence test of piribedil sustained-release tablets without sugar coating

[0055] 1. Test methods

[0056] 1.1. Preparation of Piribedil Sustained-Release Tablets of Comparative Example 1

[0057] 1.1.1 Prescription

[0058]

[0059]

[0060] 1.1.2 Preparation method

[0061] (1) dissolving a prescribed amount of povidone K30 in purified water to prepare an adhesive aqueous solution with a concentration of 20%;

[0062] (2) weighing the prescribed amount of micronized piribedil and talc, and using the binder solution obtained in step (1) to form granules through a fluidized bed process; during the spraying process, the inlet air temperature of the fluidized bed is controlled at 38-48° C., and after the spraying is completed, the inlet air temperature is increased to dry the granules, and the material temperature is heated to 50° C. and maintained for 10-20 minutes until the drying loss is no more than 2.0%;

[0063] (3) The particles obtained in step (2) are sized by a pulverizer with a pulverizing screen size of 1 mm, and the sized particles are mixed with a prescribed amount of magnesium stearate in a mixer for 5 minutes to obtain a total mixture;

[0064] (4) The total mixture obtained in step (3) is tableted using a high-speed rotary tablet press, and an 8 mm shallow concave punch is selected for tableting, thereby obtaining the piribedil sustained-release tablets of Comparative Example 1, wherein the core hardness of the tablet is controlled at 50-100 N, and the friability does not exceed 1.0%.

[0065] 1.2. In vitro dissolution test

[0066] The import registration standard test method and the test method of the present invention were used to measure the comparison example 1 and the original reference preparation. The in vitro dissolution release of (50 mg specification) is as follows:

[0067] Import registration standard release determination method: According to the second dissolution method apparatus (paddle method) specified in the General Rules 0931 of the Fourth Part of the 2020 Edition of the Chinese Pharmacopoeia, the rotation speed is 100rpm, the release medium is 1000ml of 0.1N hydrochloric acid solution, and the dissolution medium temperature is 37℃±0.5℃. Sample 10ml of solution after 2, 4, 8 and 16 hours, filter and immediately add 10ml of the above medium. Take the subsequent filtrate as the test solution, detect the cumulative dissolution at each time point, and calculate the dissolution similarity factor f2 between Comparative Example 1 and the reference preparation.

[0068] Release determination method of the present invention: according to the seventh dissolution method apparatus (reciprocating cylinder method) specified in the general rules 0931 of the fourth part of the 2020 edition of the Chinese Pharmacopoeia, the reciprocating frequency is 20dpm, the release medium is 250ml of 0.1N hydrochloric acid solution, and the dissolution medium temperature is 37°C ± 0.5°C. Samples were taken at 0.5, 1, 2, 3, 4, 6 and 8 hours, 5ml of solution was sampled each time, filtered with a 0.45μm filter membrane, and 5ml of the above medium was added immediately. The subsequent filtrate was taken as the test solution, the cumulative dissolution at each time point was detected, and the dissolution similarity factor f2 between Comparative Example 1 and the reference preparation was calculated.

[0069] 1.3. In vivo bioavailability test

[0070] A single-center, randomized, open, single-dose, two-drug, four-cycle, two-sequence completely repeated crossover design was used for a human bioequivalence study of fasting administration. All enrolled subjects were randomly divided into Group I and Group II, with equal numbers of people in each group. Each subject took one of the test preparations (T) or reference preparations (R) per cycle, and the drug was administered only once per cycle. The washout period was 7 days. Blood samples were collected at 0 hour (within 60 minutes) before administration and 0.25 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 20 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours and 72 hours after administration to calculate the original 50 mg strength. Various pharmacokinetic parameters of the piribedil sustained-release tablets (reference preparation) and the piribedil sustained-release tablets (test preparation) prepared in Comparative Example 1 under fasting conditions.

[0071] 2. Test results

[0072] 2.1. In vitro dissolution test results

[0073] The in vitro dissolution release data of Comparative Example 1 and the original reference preparation measured by the import registration standard and the detection method of the present invention are shown in Table 1 below.

[0074] Table 1 Dissolution data of comparative example 1 and original reference preparation measured by two detection methods

[0075]

[0076] 2.2. In vivo bioavailability test results

[0077] The bioequivalence results of Comparative Example 1 and the original reference preparation under fasting conditions are shown in Table 2 below.

[0078] Table 2 In vivo pharmacokinetic parameter data of comparative example 1 and reference preparation

[0079]

[0080] The above comparative example 1 adopts and original preparation ( Tablets) similar to the formula design, that is, talcum powder is used as a sustained-release material to control drug release, the main difference is that comparative example 1 does not use sugar coating. Considering that sugar coating does not affect drug release under normal circumstances, and the sugar coating process is relatively complex and time-consuming, the batch-to-batch difference is large, and product quality control is difficult, the design scheme without sugar coating was first adopted in the early formulation design. From the results of the in vitro dissolution similarity factor f2 of comparative example 1 and the original preparation measured by the registration standard method in Table 1 is greater than 50, the possibility of bioequivalence between the two in vivo is relatively large, but surprisingly, the in vivo pharmacokinetic results in Table 2 show that the AUC ratio of comparative example 1 and the original preparation and its 90% confidence interval do not meet the requirements of bioequivalence, indicating that comparative example 1 without sugar coating is not biologically equivalent to the original preparation, which may be related to the excessively high variation of the original product in vivo.

[0081] In addition, in order to better guide the prescription adjustment, the present invention has developed a new dissolution determination method. The results in Table 1 show that the dissolution similarity factor f2 of Comparative Example 1 and the original preparation measured by the newly developed dissolution determination method of the present invention is less than 50, indicating that the release curves of the two in vitro are not similar, which is consistent with the results of the actual biological inequality of the two in vivo recorded in Table 2, indicating that the new dissolution determination method developed by the present invention is significantly superior to the detection method of the original registration standard in terms of discrimination ability. Therefore, the subsequent experiments of the present invention all use the newly developed determination method to determine the dissolution of the examples / comparative examples and the original preparation.

[0082] Test Example 2: In vitro dissolution test of original preparation and original preparation tablet core

[0083] 1. Test methods

[0084] In order to further study the effect of sugar coating on the dissolution rate of the original preparation, this test example refers to the "release determination method of the present invention" described in Section 1.2 of Test Example 1, and the original reference preparation ( Tablets) and the original reference preparation without sugar coating ( The cumulative dissolution rate of the original formulation and the tablet core) at each time point was calculated, and the dissolution similarity factor f2 of the original formulation and the tablet core was calculated.

[0085] 2. Test results

[0086] The in vitro dissolution release data of the original preparation and the original preparation tablet core measured by the detection method of the present invention are shown in Table 3 below.

[0087] Table 3 Dissolution data of original preparation and original preparation tablet core determined by the detection method of the present invention

[0088]

[0089] As can be seen from Table 3 above, the in vitro dissolution similarity factor f2 of the original formulation and the original formulation tablet core is only 43, indicating that the release behavior of the two in vitro is less similar, confirming that sugar coating is an important reason for the high variability of drug release in vivo.

[0090] Test Example 3: In vitro dissolution test of piribedil sustained-release tablets containing sustained-release materials

[0091] 1. Test methods

[0092] 1.1. Preparation of Piribedil Sustained-Release Tablets of Examples 1-2 and Comparative Example 2

[0093] 1.1.1 Prescription

[0094]

[0095] 1.1.2 Preparation method

[0096] (1) dissolving a prescribed amount of povidone K30 in purified water to prepare an adhesive aqueous solution with a concentration of 20%;

[0097] (2) weighing the prescribed amount of micronized piribedil, talc and sustained-release material (hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose E4M or hydroxyethyl cellulose 250M), and using the binder solution obtained in step (1) to form granules through a fluidized bed process; during the spraying process, the inlet air temperature of the fluidized bed is controlled at 38-48° C., and after the spraying is completed, the inlet air temperature is increased to dry the granules, and the material temperature is heated to 50° C. and maintained for 10-20 minutes until the drying loss is no more than 2.0%;

[0098] (3) The particles obtained in step (2) are sized by a pulverizer with a pulverizing screen size of 1 mm, and the sized particles are mixed with a prescribed amount of lubricant magnesium stearate in a mixer for 5 minutes to obtain a total mixture;

[0099] (4) The total mixture obtained in step (3) is tableted using a high-speed rotary tablet press, and an 8 mm shallow concave punch is selected for tableting to obtain the piribedil sustained-release tablets of Examples 1-2 and Comparative Example 2, wherein the core hardness of the tablet is controlled at 50-100 N and the friability does not exceed 1.0%.

[0100] 1.2. In vitro dissolution test

[0101] The detection method of the present invention described in Test Example 1 was used to determine the The in vitro dissolution release of the 50 mg formulation was calculated, and the dissolution similarity factor f2 of Examples 1-2, Comparative Example 2 and the original reference preparation was calculated.

[0102] 2. Test results

[0103] The in vitro dissolution release data of Examples 1-2, Comparative Example 2 and the original reference preparation measured by the detection method of the present invention are shown in Table 4 below.

[0104] Table 4 Dissolution data of Examples 1-2, Comparative Example 2 and original reference preparations measured by the detection method of the present invention

[0105]

[0106] On the basis of selecting talcum powder as the sustained-release material in Comparative Example 1, the same amount of cellulose derivative sustained-release materials with similar viscosity were added to prepare piribedil sustained-release tablets containing composite sustained-release materials (Comparative Examples 2-3 and Example 1). The test results of Table 4 above show that the dissolution similarity factor f2 of the sustained-release tablets of Example 1-2, which selects hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose E4M and talcum powder in combination, and the original reference preparation is greater than 50, indicating that the selection of hydroxypropyl methylcellulose sustained-release materials can obtain an in vitro dissolution similar to the original preparation. In comparison, the dissolution similarity factor f2 of the sustained-release tablet of Comparative Example 2, which selects hydroxyethyl cellulose 250M and talcum powder in combination, and the original reference preparation is less than 50, and it is expected that it cannot achieve bioequivalence with the original reference preparation in vivo.

[0107] Test Example 4: In vitro dissolution test of piribedil sustained-release tablets containing different amounts of sustained-release materials

[0108] 1. Test methods

[0109] 1.1. Preparation of Piribedil Sustained-Release Tablets of Example 2-5

[0110] 1.1.1 Prescription

[0111]

[0112] 1.1.2 Preparation method

[0113] The same preparation method as in Section 1.1.2 of Experimental Example 3.

[0114] 1.2. In vitro dissolution test

[0115] The detection method of the present invention described in Test Example 1 was used to determine the The in vitro dissolution release of the 50 mg formulation was calculated, and the dissolution similarity factor f2 between Examples 2-5 and the reference formulation was calculated.

[0116] 1.3. In vivo bioavailability test

[0117] The method in Section 1.3 of Test Example 1 was used to determine and calculate the original 50 mg specification. Various pharmacokinetic parameters of the piribedil sustained-release tablets (reference preparation) and the piribedil sustained-release tablets (test preparation) prepared in Example 5 under fasting and postprandial conditions.

[0118] 2. Test results

[0119] 2.1. In vitro dissolution test results

[0120] The in vitro dissolution release data of Examples 2-5 and the original reference preparation measured by the detection method of the present invention are shown in Table 5 below.

[0121] Table 5 Dissolution data of Examples 2-5 and original reference preparations measured by the detection method of the present invention

[0122]

[0123] On the basis of Example 2, the effect of the dosage of HPMC E4M on the release of the sustained-release tablets was further investigated. As shown in the test results of Table 5, when the ratio of talc to HPMC E4M was in the range of 2.5:1 to 6:1, the dissolution similarity factor f2 of the sustained-release tablets and the original preparation was greater than or equal to 50, which met the test requirements of in vitro dissolution.

[0124] 2.2 In vivo bioequivalence

[0125] Table 6 In vivo pharmacokinetic parameter data of Example 5 and reference preparation

[0126]

[0127] It can be seen from Table 6 above that Example 5 and the original reference preparation achieve in vivo bioequivalence. Combined with the result of in vitro dissolution similarity factor f2 of up to 71 in Table 5, it is verified again that the effect of dissolution data obtained by the new detection method of the present invention in predicting in vivo bioequivalence is significantly better than the detection method of the import registration standard.

[0128] Although specific embodiments of the present invention have been described, it will be appreciated by those skilled in the art that various changes and modifications may be made to the present invention without departing from the scope or spirit of the present invention. Therefore, the present invention is intended to cover all such changes and modifications that fall within the scope of the appended claims and their equivalents.

Claims

1. A piribedil sustained-release tablet, characterized in that: The sustained-release tablet comprises piribedil, talc, a sustained-release material, a binder and a lubricant, wherein the sustained-release material is hypromellose, and the sustained-release tablet is different from the original reference preparation. The dissolution similarity factor f2 is greater than or equal to 50.

2. The piribedil sustained-release tablet according to claim 1, characterized in that The sustained-release tablet does not include any coating layer.

3. The piribedil sustained-release tablet according to claim 1, characterized in that The hypromellose is selected from one or more of hypromellose E4M and hypromellose K4M.

4. The piribedil sustained-release tablet according to claim 1, characterized in that The weight ratio of the talc to the hypromellose is 1:1-10:

1.

5. The piribedil sustained-release tablet according to claim 1, characterized in that: The binder is selected from one or more of povidone, low-substituted hydroxypropyl cellulose and starch.

6. The piribedil sustained-release tablet according to claim 1, characterized in that: The lubricant is selected from one or more of magnesium stearate, micro powder silica gel and talc.

7. The piribedil sustained-release tablet according to claim 1, characterized in that: Piribedil is micronized.

8. The method for preparing the piribedil sustained-release tablet according to any one of claims 1 to 7, characterized in that: The preparation method comprises the following steps: (1) dissolving a prescribed amount of adhesive in purified water to prepare an adhesive solution; (2) weighing the prescribed amount of piribedil, talc and sustained-release material, and using the binder solution obtained in step (1) to prepare granules through a fluidized bed process; (3) The particles obtained in step (2) are sized by a pulverizer, and the sized particles are mixed with a prescribed amount of lubricant in a mixer to obtain a total mixture; (4) tabletting the total mixture obtained in step (3) using a high-speed rotary tablet press to obtain the product.

9. Use of the piribedil sustained-release tablet according to any one of claims 1 to 7 in the preparation of a medicament for treating Parkinson's disease.

10. A method for determining the in vitro dissolution rate of the piribedil sustained-release tablet according to any one of claims 1 to 7, characterized in that: The determination method is the dissolution method 7 reciprocating cylinder method specified in General Chapter 0931 of Part IV of the 2020 edition of the Chinese Pharmacopoeia.

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