Oxcarbazepine sustained release tablet and preparation method thereof

Abstract

The invention relates to an oxcarbazepine sustained-release tablet, the sustained-release tablet comprises a sustained-release tablet core, the sustained-release tablet core comprises oxcarbazepine, a filler, a sustained-release material and a release regulator, and the release regulator is fatty acid. According to the oxcarbazepine sustained release preparation disclosed by the invention, a stable skeleton system is selected, and fatty acid is added as a release regulator, so that the cost is saved, and the burst release risk caused by food effect and gastric juice pH change after a preparation product enters a body is avoided; and the effect of bioequivalence with a commercially available product OXTELLAR # imgabs0 # under two conditions of empty stomach and after meal is successfully realized.

Description

Technical Field

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

[0002] Oxcarbazepine belongs to the benzodiazepine class of drugs and is clinically used to treat localized and generalized epileptic seizures in adults and children over 6 years old. Currently, the dosage forms of oxcarbazepine available in China and abroad include suspension, immediate-release tablets and sustained-release tablets. In 2012, the FDA approved the product produced by SUPERNUS under the trade name OXTELLAR The company's oxcarbazepine sustained-release tablets are now available in 150mg, 300mg and 600mg strengths.

[0003] Original product OXTELLAR Color coating is applied to matrix tablets. Since oxcarbazepine has poor solubility and cannot be completely released from the sustained-release dosage form, OXTELLAR In its skeleton tablet core, not only a large amount of surfactant is used for solubilization, but also up to 10% of pH-dependent / enteric polymer Eudragit L100-55 is added as a release enhancer. The purpose is that when the preparation is exposed to an aqueous medium with a pH below 4.0, it will not be affected. When exposed to an aqueous medium with a pH above 4.0, the enteric polymer will dissolve rapidly, increasing the contact surface between the aqueous medium and the slightly soluble drug, thereby enhancing the drug release rate and improving the bioavailability of oxcarbazepine.

[0004] The original product uses a large amount of pH-dependent / enteric polymers, which makes it more affected by food. When taken on an empty stomach or after a meal, its peak concentration C max The area under the curve (AUC) will be significantly different when the drug is taken and the AUC is significantly affected after taking the drug. max In order to make the oxcarbazepine sustained-release preparation maintain the same food effect as the original product and achieve bioequivalence with the original product both on an empty stomach and after eating, the use of pH-dependent / enteric polymers is particularly critical. Bioequivalence related literature reports. 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 an oxcarbazepine sustained-release tablet, which comprises a sustained-release tablet core, wherein the sustained-release tablet core comprises oxcarbazepine, a filler, a sustained-release material and a release regulator, and the release regulator is a fatty acid.

[0007] Preferably, the weight percentage of oxcarbazepine in the sustained-release tablet core is 50%-70%. More preferably, the weight percentage of oxcarbazepine in the sustained-release tablet core is 55%-65%. Further preferably, the weight percentage of oxcarbazepine in the sustained-release tablet core is 60%.

[0008] Preferably, the particle size D of oxcarbazepine is 90 More preferably, the particle size D of oxcarbazepine is 90 Less than 200 μm. Further preferably, the particle size D of oxcarbazepine 90 Less than 150μm.

[0009] Preferably, the filler is a composition of a first filler and a second filler, wherein the first filler is selected from one or more of microcrystalline cellulose, silicified microcrystalline cellulose, and calcium hydrogen phosphate, and the second filler is selected from one or more of lactose, sucrose, and mannitol, and the weight ratio of the first filler to the second filler is 1:1-5:1. More preferably, the filler is a composition of microcrystalline cellulose and lactose in a weight ratio of 1:1-3:1. Further preferably, the filler is a composition of microcrystalline cellulose and lactose in a weight ratio of 1:1-2:1. Further preferably, the filler is a composition of microcrystalline cellulose and lactose in a weight ratio of 1.25:1.

[0010] Preferably, the weight percentage of the filler in the sustained-release core is 10%-30%. More preferably, the weight percentage of the filler in the sustained-release core is 15%-25%. Further preferably, the weight percentage of the filler in the sustained-release core is 15%-20%. Further preferably, the weight percentage of the filler in the sustained-release core is 18%.

[0011] Preferably, the sustained-release material is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, sodium alginate, carbomer or polyoxyethylene. More preferably, the sustained-release material is hydroxypropyl methylcellulose. Further preferably, the sustained-release material is hydroxypropyl methylcellulose K4M.

[0012] Preferably, the weight percentage of the sustained-release material in the sustained-release core is 5%-25%. More preferably, the weight percentage of the sustained-release material in the sustained-release core is 10%-20%. Further preferably, the weight percentage of the sustained-release material in the sustained-release core is 10%-15%. Further preferably, the weight percentage of the sustained-release material in the sustained-release core is 12%.

[0013] Preferably, the fatty acid is selected from one or more of stearic acid, palmitic acid, oleic acid, and myristic acid. More preferably, the fatty acid is selected from one or more of stearic acid and palmitic acid. Further preferably, the fatty acid is stearic acid.

[0014] Preferably, the release modifier is all added after the granulation process. More preferably, a portion of the release modifier is added during the granulation process (internal addition), and the other portion is added after the granulation process (external addition).

[0015] Preferably, the weight percentage of the release regulator in the sustained-release tablet core is 1%-15%. More preferably, the weight percentage of the release regulator in the sustained-release tablet core is 4%-10%. Further preferably, the weight percentage of the release regulator in the sustained-release tablet core is 7%.

[0016] Preferably, the release modifier includes an internal release modifier in the particle and an external release modifier outside the particle, and the weight ratio of the internal release modifier to the external release modifier is 1:1-10:1. More preferably, the weight ratio of the internal release modifier to the external release modifier is 4:1-8:1. Further preferably, the weight ratio of the internal release modifier to the external release modifier is 6:1.

[0017] Preferably, the sustained-release tablet core further comprises a solubilizer.

[0018] Preferably, the solubilizing agent is selected from one or more of sodium lauryl sulfate, sodium docusate, polysorbate, sodium lauryl sulfate, poloxamer, and polyvinyl pyrrolidone. More preferably, the solubilizing agent is selected from one or more of sodium lauryl sulfate, sodium docusate, and polysorbate. Further preferably, the solubilizing agent is sodium lauryl sulfate.

[0019] Preferably, the weight percentage of the solubilizer in the sustained-release tablet core is 1%-5%. More preferably, the weight percentage of the solubilizer in the sustained-release tablet core is 2%-4%. Further preferably, the weight percentage of the solubilizer in the sustained-release tablet core is 3%.

[0020] Preferably, the sustained-release tablet further comprises a coating layer, and the coating layer comprises a color coating material.

[0021] Preferably, the color coating material is Opadry.

[0022] Preferably, the weight percentage of the color coating material in the sustained-release core is 1%-10%. More preferably, the weight percentage of the color coating material in the sustained-release core is 2%-6%. Further preferably, the weight percentage of the color coating material in the sustained-release core is 4%.

[0023] Preferably, the oxcarbazepine sustained-release tablets contain 600 mg oxcarbazepine, 100 mg microcrystalline cellulose, 80 mg lactose, 120 mg hydroxypropyl methylcellulose K4M, 30 mg sodium lauryl sulfate, 70 mg stearic acid and 40 mg Opadry color coating material, and the sustained-release tablets are compressed after a granulation process, wherein 60 mg stearic acid is added during the granulation process, and 10 mg stearic acid is added after the granulation process.

[0024] Preferably, the oxcarbazepine sustained-release tablets contain 600 mg oxcarbazepine, 130 mg microcrystalline cellulose, 80 mg lactose, 120 mg hydroxypropyl methylcellulose K4M, 30 mg sodium lauryl sulfate, 40 mg stearic acid and 40 mg Opadry color coating material, and the sustained-release tablets are compressed after a granulation process, and the stearic acid is added after the granulation process.

[0025] Preferably, the oxcarbazepine sustained-release tablets contain 600 mg oxcarbazepine, 70 mg microcrystalline cellulose, 80 mg lactose, 120 mg hydroxypropyl methylcellulose K4M, 30 mg sodium lauryl sulfate, 100 mg stearic acid and 40 mg Opadry color coating material, and the sustained-release tablets are compressed after a granulation process, and the stearic acid is added after the granulation process.

[0026] Preferably, the oxcarbazepine sustained-release tablets are similar to the commercially available preparation Oxtellar The in vitro dissolution similarity factor f2 is greater than 50. More preferably, the oxcarbazepine sustained-release tablet is similar to the commercially available preparation Oxtellar The in vitro dissolution similarity factor f2 is greater than 55. Further preferably, the oxcarbazepine sustained-release tablets are similar to the commercially available preparation Oxtellar The in vitro dissolution similarity factor f2 is greater than 60. Further preferably, the oxcarbazepine sustained-release tablets are similar to the commercially available preparation Oxtellar The in vitro dissolution similarity factor f2 is greater than 65. Further preferably, the oxcarbazepine sustained-release tablets are similar to the commercially available preparation Oxtellar The in vitro dissolution similarity factor f2 is greater than 70.

[0027] Preferably, the oxcarbazepine sustained-release tablets are similar to the commercially available preparation Oxtellar Biological equivalence.

[0028] The second aspect of the present invention provides a method for preparing the above-mentioned oxcarbazepine sustained-release tablets, the preparation method comprising the following steps:

[0029] (1) adding oxcarbazepine, filler, sustained-release material, solubilizer and optional release modifier into a high-efficiency wet granulator, spraying purified water into the granulator to form wet granules, and drying the wet granules in a fluidized bed or oven;

[0030] (2) The granules dried in step (1) are granulated by a pulverizer, and the remaining release modifier is added to the pulverized granules, and the pulverized granules are mixed in a mixer to obtain a total mixture;

[0031] (3) tableting the total mixture obtained in step (2) to obtain drug-containing sustained-release tablet cores;

[0032] (4) The color coating material is prepared into a coating solution with purified water, and the coating is performed on the drug-containing sustained-release tablet core to obtain the product.

[0033] Preferably, the coating solution in step (4) is a 15% concentration aqueous solution of a color coating material.

[0034] The third aspect of the present invention provides the use of the above-mentioned oxcarbazepine sustained-release tablets in the preparation of drugs for treating epilepsy and convulsions.

[0035] The fourth aspect of the present invention provides a method for determining the in vitro dissolution rate of the above-mentioned oxcarbazepine sustained-release tablets, wherein the determination method is a paddle method, and the dissolution medium is divided into a three-step method, wherein the sample to be tested is first released in a pH 1.2 dissolution medium for 2 hours, then transferred to a pH 5.8 dissolution medium for release for 2 hours, and finally transferred to a pH 6.8 dissolution medium for release until the last time point.

[0036] Preferably, the pH 1.2 dissolution medium is a pH 1.2 hydrochloride buffer, the pH 5.8 dissolution medium is a pH 5.8 phosphate buffer, and the pH 6.8 dissolution medium is a pH 6.8 phosphate buffer containing 1% sodium dodecyl sulfate.

[0037] Preferably, the volume of the dissolution medium is 900 mL, the rotation speed is 75 rpm, and the temperature of the dissolution medium is 37°C ± 0.5°C.

[0038] Preferably, the sampling time points of the determination method are 1 h, 2 h, 4 h, 6 h, 8 h and 10 h respectively.

[0039] The fifth aspect of the present invention provides an application of a release regulator in adjusting the release rate of the above-mentioned oxcarbazepine sustained-release tablets, wherein the release regulator is a fatty acid, and the oxcarbazepine sustained-release tablets are different from the commercially available preparation Oxtellar The in vitro dissolution similarity factor f2 is greater than 50.

[0040] Preferably, the fatty acid as the release modifier is selected from one or more of stearic acid, palmitic acid, oleic acid, and myristic acid. More preferably, the fatty acid as the release modifier is selected from one or more of stearic acid and palmitic acid. Further preferably, the fatty acid as the release modifier is stearic acid.

[0041] Preferably, the release modifier is all added after the granulation process. More preferably, a portion of the release modifier is added during the granulation process (internal addition), and the other portion is added after the granulation process (external addition).

[0042] Preferably, the weight percentage of the release regulator in the sustained-release tablet core is 1%-15%. More preferably, the weight percentage of the release regulator in the sustained-release tablet core is 4%-10%. Further preferably, the weight percentage of the release regulator in the sustained-release tablet core is 7%.

[0043] Preferably, the release modifier includes an internal release modifier in the particle and an external release modifier outside the particle, and the weight ratio of the internal release modifier to the external release modifier is 1:1-10:1. More preferably, the weight ratio of the internal release modifier to the external release modifier is 4:1-8:1. Further preferably, the weight ratio of the internal release modifier to the external release modifier is 6:1.

[0044] Preferably, the oxcarbazepine sustained-release tablets are similar to the commercially available preparation Oxtellar The in vitro dissolution similarity factor f2 is greater than 55. More preferably, the oxcarbazepine sustained-release tablet is similar to the commercially available preparation Oxtellar The in vitro dissolution similarity factor f2 is greater than 60. Further preferably, the oxcarbazepine sustained-release tablets are similar to the commercially available preparation Oxtellar The in vitro dissolution similarity factor f2 is greater than 65. Further preferably, the oxcarbazepine sustained-release tablets are similar to the commercially available preparation Oxtellar The in vitro dissolution similarity factor f2 is greater than 70.

[0045] The technical effects produced by the present invention are:

[0046] The oxcarbazepine sustained-release preparation of the present invention does not use a large amount of pH-dependent polymers in the tablet core formulation to form pores to promote release, but uses a more robust skeleton system and creatively adds fatty acids (such as stearic acid) as release regulators, which not only saves costs but also avoids the risk of sudden release of the preparation product due to food effect and changes in gastric juice pH after entering the body, and successfully achieves the same effect as the commercially available product OXTELLAR Excellent bioequivalence under both fasting and fed conditions. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 The results of in vitro dissolution tests of Comparative Example 1 and the original reference preparation in different dissolution media are shown;

[0048] Figure 2 The dissolution test results of Comparative Example 1 and the original reference preparation in the three-step dissolution method of the present invention are shown;

[0049] Figure 3 The dissolution test results of Examples 1-2 and the original reference preparation in the three-step dissolution method of the present invention;

[0050] Figure 4 These are the dissolution test results of Example 3 and the original reference preparation in the three-step dissolution method of the present invention. DETAILED DESCRIPTION

[0051] Test Example 1: In vitro dissolution and in vivo bioequivalence test of oxcarbazepine sustained-release tablets with low content of release modifier

[0052] 1. Test methods

[0053] 1.1. Preparation of Oxcarbazepine Sustained-Release Tablets of Comparative Example 1

[0054] 1.1.1 Prescription

[0055]

[0056]

[0057] 1.1.2 Preparation method

[0058] Oxcarbazepine, microcrystalline cellulose, lactose, hypromellose K4M and sodium lauryl sulfate were added to a high-efficiency wet granulator, the stirring blade and the cutting blade were turned on, and the mixture was premixed for 5 minutes, and then purified water was sprayed in for granulation. After the granulation was completed, the material was transferred to a fluidized bed for drying. The dried granules were crushed, mixed with stearic acid to obtain a total mixture, and then tableted on a rotary tablet press, and finally color coated with a 15% concentration of a color coating material aqueous solution to obtain the oxcarbazepine sustained-release tablets of Comparative Example 1.

[0059] 1.2. In vitro dissolution assay

[0060] The paddle method (using a sinker) was used to measure the comparative example 1 and the original reference preparation Oxtellar The in vitro dissolution of the drug (600 mg specification) was measured in 900 mL of phosphate buffer solution containing 1.5% sodium dodecyl sulfate (SDS), pH 1.2, phosphate buffer solution containing 1% sodium dodecyl sulfate, and pH 6.8 phosphate buffer solution containing 1% sodium dodecyl sulfate, respectively. The speed was 75 rpm and the dissolution medium temperature was 37°C ± 0.5°C. In the above three dissolution media, samples were taken at 1h, 2h, 4h, 6h, 8h and 10h, respectively, with a sampling volume of 10mL. The drug content was determined according to the following HPLC conditions: chromatographic column: 4.6mm x150mm, 3.5μm; flow rate: 1.2mL / min; detector: ultraviolet 306nm; injection volume: 5μL; column temperature: 30°C. The cumulative dissolution of Comparative Example 1 and the original reference preparation at each time point and the dissolution similarity factor f2 between Comparative Example 1 and the reference preparation were calculated.

[0061] 1.3. In vivo bioequivalence testing

[0062] A single-center, randomized, open, single-dose, two-drug, two-period crossover design was used for a fasting human bioequivalence study. 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 120 minutes) before administration and 1 hour, 2 hours, 3 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours, 8.5 hours, 9 hours, 10 hours, 11 hours, 12 hours, 14 hours, 16 hours, 20 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours and 72 hours after administration to calculate the 600mg strength of Oxtellar Various pharmacokinetic parameters (C max , AUC 0-t and AUC 0-∞ ).

[0063] 2. Test results

[0064] 2.1. In vitro dissolution test results

[0065] Comparative Example 1 uses HPMC K4M as a sustained-release material to control drug release, and selects 0.5% of stearic acid as a release regulator to adjust the dissolution rate of the drug at each stage. The dissolution rates of Comparative Example 1 and the original reference preparation in three dissolution media were determined by conventional dissolution methods. The specific test results are shown in Figure 1The test results show that in three different dissolution media, the dissolution similarity factors f2 of Comparative Example 1 and the reference preparation are 58, 88 and 65, respectively, indicating that Comparative Example 1 is expected to be bioequivalent to the reference preparation in vivo.

[0066] 2.2. In vivo bioavailability test results

[0067] The oxcarbazepine sustained-release tablets of comparative example 1 and the original formulation Oxtellar The pharmacokinetic parameters of the drug (600 mg) under fasting and postprandial conditions are shown in Table 1 below.

[0068] Table 1 In vivo pharmacokinetic parameter data of comparative example 1 and original preparation

[0069]

[0070] The in vivo test results in Table 1 above show that the oxcarbazepine sustained-release tablets of Comparative Example 1 are equivalent to the original reference preparation under fasting conditions, but the post-meal release is significantly slower than the reference preparation, and the pharmacokinetic data of fasting and post-meal are quite different, indicating that it is difficult to achieve bioequivalence with the reference preparation under both fasting and post-meal conditions with the low content (0.5% of the tablet core weight) of the release regulator stearic acid added in Comparative Example 1. In addition, the inconsistent results of the above in vitro and in vivo tests also show that the conventional in vitro dissolution determination method is not effective in predicting the in vivo bioequivalence of the test preparation and the reference preparation.

[0071] Test Example 2: Determination of the "three-step" dissolution determination method of the present invention

[0072] 1. Test methods

[0073] The test results of Test Example 1 show that the conventional dissolution determination method cannot effectively predict the in vivo release of oxcarbazepine sustained-release tablets under fasting and postprandial conditions. Therefore, this test example adjusts the one-step dissolution to a three-step dissolution (other dissolution conditions remain unchanged) to better simulate the in vivo release of the drug. That is, Comparative Example 1 and the reference preparation are first released under pH 1.2 hydrochloride aqueous solution conditions for 2 hours, then transferred to pH 5.8 phosphate aqueous solution conditions for 2 hours, and finally transferred to pH 6.8 phosphate buffer containing 1% SDS until the last time point.

[0074] 2. Test results

[0075] The dissolution data of Comparative Example 1 and the reference preparation were determined by a three-step dissolution method. Figure 2 As shown. The test results show that the dissolution of the reference preparation shows an S-shaped release curve, that is, it is slow at first, then fast and finally becomes stable. The dissolution curve of Comparative Example 1 does not have the characteristics of S-shaped release. Its release rate in the acidic dissolution medium is faster than that of the reference preparation in the early stage, and its release rate at pH 6.8 is slower than that of the reference preparation in the later stage (see Figure 2 ). It has been verified in Test Example 1 that the in vivo bioequivalence results of Comparative Example 1 show that the release rate is slightly faster under fasting conditions and slightly slower under fed conditions, which is consistent with the trend of the three-step dissolution data. Therefore, the three-step dissolution determination method can better predict the drug release of the preparation in vivo.

[0076] Experimental Example 3: Effects of different contents of stearic acid on the in vitro release of oxcarbazepine sustained-release tablets

[0077] 1. Test methods

[0078] 1.1. Preparation of Oxcarbazepine Sustained-Release Tablets of Example 1-2

[0079] 1.1.1 Prescription

[0080] In order to obtain an S-shaped curve similar to that of the reference preparation, this test example attempts to adjust the amount of the release regulator in the sustained-release tablets. The adjusted prescription of oxcarbazepine sustained-release tablets is shown in the following table.

[0081]

[0082] 1.1.2 Preparation method

[0083] Oxcarbazepine, microcrystalline cellulose, lactose, hypromellose K4M and sodium lauryl sulfate were added to a high-efficiency wet granulator, the stirring blade and the cutting blade were turned on, and premixed for 5 minutes, and then purified water was sprayed in for granulation. After the granulation was completed, the material was transferred to a fluidized bed for drying. The dried granules were crushed, mixed with stearic acid to obtain a total mixture, and then tableted on a rotary tablet press, and finally color coated with a 15% concentration of a color coating material aqueous solution to obtain the oxcarbazepine sustained-release tablets of Example 1-2.

[0084] 1.2. In vitro dissolution assay

[0085] Referring to the dissolution determination method of Test Example 2, the paddle method (using a sinker) was used to determine the dissolution of Examples 1-2 and the original reference preparation Oxtellar The in vitro dissolution of the drug (600 mg specification) was measured in a conversion solvent (first at pH 1.2 hydrochloride aqueous solution for 2 h, then at pH 5.8 phosphate aqueous solution for 2 h, and finally at pH 6.8 phosphate buffer containing 1% SDS until the last time point), the rotation speed was 75 rpm, and the dissolution medium temperature was 37°C ± 0.5°C. Samples were taken in the three dissolution media at 1 h, 2 h, 4 h, 6 h, 8 h, and 10 h, respectively, with a sampling volume of 10 mL, and the drug content was determined according to the following HPLC conditions: chromatographic column: 4.6 mm x 150 mm, 3.5 μm; flow rate: 1.2 mL / min; detector: UV 306 nm; injection volume: 5 μL; column temperature: 30°C. The cumulative dissolution of Example 1-2 and the original reference preparation at each time point and the dissolution similarity factor f2 between Example 1-2 and the reference preparation were calculated.

[0086] 2. Test results

[0087] Under the three-step dissolution conditions of this test example, the dissolution rates of the oxcarbazepine sustained-release tablets of Examples 1-2 were compared with those of the reference preparation. The test results showed that Examples 1-2, with different amounts of stearic acid added (accounting for 4%-10% of the sustained-release tablet core weight), all showed an S-shaped release curve that was consistent with the reference preparation (see Figure 3 ), that is, a characteristic release curve of slow release at the beginning, rapid release, and finally slow release. In addition, the in vitro dissolution similarity factors f2 of Example 1-2 and the reference preparation were 66 and 74, respectively, confirming that the in vitro dissolution of the oxcarbazepine sustained-release tablets of Example 1-2 was similar to that of the original reference preparation.

[0088] Experimental Example 4: Effects of internal and external stearic acid on the in vitro release of oxcarbazepine sustained-release tablets

[0089] 1. Test methods

[0090] 1.1. Preparation of Oxcarbazepine Sustained-Release Tablets of Example 3

[0091] 1.1.1 Prescription

[0092] The formulation of Example 1-2 was further optimized by adjusting the addition method of stearic acid to a combination of internal addition and external addition, in order to improve the fluidity and compressibility of the particles during the preparation of the sustained-release tablets. The adjusted formulation of oxcarbazepine sustained-release tablets is as follows.

[0093]

[0094]

[0095] 1.1.2 Preparation method

[0096] Oxcarbazepine, microcrystalline cellulose, lactose, hypromellose, sodium lauryl sulfate and part of stearic acid (added internally) are added to a high-efficiency wet granulator, the stirring blade and the cutting blade are turned on, premixed for 5 minutes, and then purified water is sprayed in for granulation. After the granulation is completed, the material is transferred to an oven or a fluidized bed for drying. The dried granules are crushed and mixed with the remaining stearic acid (added externally) to obtain a total mixture, which is then tableted on a rotary tablet press, and finally color coated with a color coating material aqueous solution having a concentration of 15%, to obtain the oxcarbazepine sustained-release tablets of Example 3.

[0097] 1.2. Particle flowability and compressibility test

[0098] The granular flowability of Examples 1-3 was evaluated by measuring the diameter of the disk aperture through which the total mixture of Examples 1-3 could pass using a Flodex powder flowability tester.

[0099] The total mixture of Examples 1-3 was compressed into tablets, and the maximum hardness of the tablet core that could be compressed by the particles was compared. The friability under the maximum hardness condition was measured to evaluate the compressibility of Examples 1-3.

[0100] 1.3. In vitro dissolution assay

[0101] Referring to the in vitro dissolution test method described in Section 1.2 of Test Example 3, the dissolution test results of Example 3 and the original reference preparation in the three-step dissolution medium were determined.

[0102] 1.4. In vivo bioequivalence study

[0103] Referring to the in vivo bioequivalence test described in Experimental Example 1, the 600 mg strength of Oxtellar was calculated. Various pharmacokinetic parameters (C max , AUC 0-t and AUC 0-∞ ).

[0104] 2. Test results

[0105] 2.1. Particle flowability and compressibility

[0106] The particle flowability results of Examples 1-3 are shown in Table 2 below. After further optimization based on the formulation of Examples 1-2, the aperture through which the particles of Example 3 can freely fall through the disc is significantly reduced, indicating that its flowability is significantly improved.

[0107] Table 2 Test results of particle flowability of Examples 1-3

[0108] prescription Diameter of disc hole (mm) Example 1 30 Example 2 34 Example 3 18

[0109] The hardness and friability test results of Examples 1-3 are shown in Table 3 below. After further optimization based on the formulation of Example 1-2, the hardness and friability of the particles of Example 3 are significantly better than those of Example 1-2, indicating that the compressibility thereof is significantly improved.

[0110] Table 3 Hardness and brittleness test results of Examples 1-3

[0111] prescription Maximum hardness of the tablet core that can be pressed (N) Friability (%) Example 1 159 0.3 Example 2 130 0.4 Example 3 298 0.0

[0112] 2.2 In vitro dissolution test

[0113] Under the three-step dissolution conditions of this test example, the oxcarbazepine sustained-release tablets of Example 3 were compared with the original reference preparation for dissolution. The test results showed that the dissolution of Example 3 had an S-shaped drug release curve that was consistent with the original reference preparation, that is, a characteristic release curve of slow release at the beginning, rapid release, and then slow release. In addition, the in vitro dissolution similarity factor f2 between Example 3 and the reference preparation was 69, confirming that the in vitro dissolution of the oxcarbazepine sustained-release tablets of Example 3 was similar to that of the original reference preparation.

[0114] 2.3 In vivo bioequivalence study

[0115] The oxcarbazepine sustained-release tablets of Example 3 and the original formulation Oxtellar The pharmacokinetic parameters of the drug (600 mg) under fasting and postprandial conditions are shown in Table 2 below.

[0116] Table 4 In vivo pharmacokinetic parameter data of Example 3 and original formulation

[0117]

[0118] The in vivo test results in Table 4 above show that after adding stearic acid both outside and inside the drug-containing particles, the mean value and 90% confidence interval of the ratio of the oxcarbazepine sustained-release tablets of Example 3 to the reference preparation meet the requirements, indicating that the pharmacokinetic parameters of Example 3 are equivalent to those of the original reference preparation under fasting or postprandial conditions.

[0119] 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. An oxcarbazepine sustained-release tablet, characterized in that: The sustained-release tablet comprises a sustained-release tablet core, which comprises oxcarbazepine, a filler, a sustained-release material and a release regulator, wherein the release regulator is a fatty acid.

2. The oxcarbazepine sustained-release tablet according to claim 1, characterized in that: The filler is a composition of a first filler and a second filler, wherein the first filler is selected from one or more of microcrystalline cellulose, silicified microcrystalline cellulose, and calcium hydrogen phosphate, and the second filler is selected from one or more of lactose, sucrose, and mannitol, and the weight ratio of the first filler to the second filler is 1:1-5:

1.

3. The oxcarbazepine sustained-release tablet according to claim 1, characterized in that: The sustained-release material is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, sodium alginate, carbomer or polyoxyethylene.

4. The oxcarbazepine sustained-release tablet according to claim 1, characterized in that: The fatty acid is selected from one or more of stearic acid, palmitic acid, oleic acid and myristic acid.

5. The oxcarbazepine sustained-release tablet according to claim 1, characterized in that: The weight percentage of the release regulator in the sustained-release tablet core is 1%-15%.

6. The oxcarbazepine sustained-release tablet according to claim 1, characterized in that: The sustained release tablet core also comprises a solubilizer.

7. The oxcarbazepine sustained-release tablet according to claim 1, characterized in that: The sustained-release tablet further comprises a coating layer, and the coating layer comprises a color coating material.

8. The method for preparing the oxcarbazepine sustained-release tablets according to any one of claims 1 to 7, characterized in that: The preparation method comprises the following steps: (1) adding oxcarbazepine, filler, sustained-release material, solubilizer and optional release modifier into a high-efficiency wet granulator, spraying a purified aqueous solution into the granules to form wet granules, and drying the wet granules in a fluidized bed or oven; (2) The granules dried in step (1) are granulated by a pulverizer, and the remaining release modifier is added to the pulverized granules, and the pulverized granules are mixed in a mixer to obtain a total mixture; (3) tableting the total mixture obtained in step (2) to obtain drug-containing sustained-release tablet cores; (4) The color coating material is prepared into a coating solution with purified water, and the coating is performed on the drug-containing sustained-release tablet core to obtain the product.

9. Use of the oxcarbazepine sustained-release tablets according to any one of claims 1 to 7 in the preparation of drugs for treating epilepsy and convulsions.

10. The method for determining the in vitro dissolution rate of oxcarbazepine sustained-release tablets according to any one of claims 1 to 7, characterized in that: The determination method is the paddle method, and the dissolution medium is divided into three steps. First, the sample to be tested is released in a pH 1.2 dissolution medium for 2 hours, then transferred to a pH 5.8 dissolution medium for release for 2 hours, and finally transferred to a pH 6.8 dissolution medium for release until the last time point.

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