Oxcarbazepine tablet and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to oxcarbazepine tablets and a preparation method thereof. The oxcarbazepine tablet comprises the following components in percentage by weight: 70-75% of oxcarbazepine, 15-20% of a filler, 1.8-2.3% of a first adhesive, 0.5-1% of a second adhesive, 5-7% of a disintegrating agent and 0.8-1.2% of a lubricant, wherein the first adhesive is selected from povidone; the second binder is selected from polyethylene glycol. The oxcarbazepine tablet disclosed by the invention has good dissolution performance and stability, by using the combination of povidone and polyethylene glycol adhesive and combining with screening of types and dosages of other auxiliary materials, the use of colloidal silicon dioxide as a flow aid is avoided, the risk of dust inhalation injury of the flow aid is reduced, the flowability of total mixed particles is improved, and the stability of the tablet is improved. And smooth discharging of materials in the tabletting process is ensured, and the tabletting requirement of mass production is met.

Description

Technical Field

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

[0002] Oxcarbazepine is a new antiepileptic drug and a 10-keto analog of carbamazepine. It appears as a white to off-white crystalline powder. As a prodrug, oxcarbazepine is rapidly metabolized in the body to the pharmacologically active 10,11-dihydro-10-hydroxycarbamazepine (10-monohydroxy metaboliute, MHD), which exerts its effects. Oxcarbazepine is well tolerated, has minimal toxic side effects, and exhibits minimal drug-drug interactions. It has become a first-line treatment for focal or generalized tonic-clonic seizures in adults and children. The FDA approved oxcarbazepine for marketing in the United States in 2000 and it is currently available in 40 countries and regions worldwide.

[0003] Oxcarbazepine is classified as Class IV by the BCS, a low-solubility, low-osmolarity drug. Technicians need to micronize oxcarbazepine to an extremely fine particle size to improve its dissolution rate and bioavailability. The original manufacturer's patent CN1170542C states that the median particle size of oxcarbazepine tablets is 2-12 μm and specifically discloses the tablet components. The plain tablets contain: oxcarbazepine, microcrystalline cellulose, hypromellose, crospovidone, colloidal silicon dioxide, and magnesium stearate, which is consistent with the manufacturer's US product insert.

[0004] When the inventors conducted research based on the excipients of the above-mentioned original formula, they found that although the original formula could be used to prepare a quick-release preparation that met the requirements, it had the following shortcomings: 1. The fluidity of the total mixed particles of the original formula was poor, and its fluidity needed to be further improved to meet the needs of large-scale tableting production; 2. The colloidal silica used as a glidant had a low density and was easily dispersed in the air. It was easily inhaled into the lungs during preparation production, posing a risk of inhalation dust injury.

[0005] Therefore, there is still a need to develop an oxcarbazepine tablet suitable for industrial production and a preparation method thereof. Summary of the Invention

[0006] In view of the technical problems of oxcarbazepine preparation in the prior art, the present invention provides an oxcarbazepine tablet and a preparation method thereof. The method can improve the fluidity of the total mixed particles without adding a glidant colloidal silicon dioxide, and is suitable for industrial production.

[0007] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0008] The present invention provides an oxcarbazepine tablet, which comprises the following components in weight percentage: 70-75% oxcarbazepine, 15-20% filler, 1.8-2.3% first binder, 0.5-1% second binder, 5-7% disintegrant, and 0.8-1.2% lubricant; wherein the first binder is selected from povidone; and the second binder is selected from polyethylene glycol.

[0009] In some embodiments, the filler is selected from one or more of lactose, sucrose, starch, pregelatinized starch, dextrin, mannitol, sorbitol, and microcrystalline cellulose.

[0010] In some embodiments, the filler is microcrystalline cellulose.

[0011] In some embodiments, the first binder is povidone K30, povidone K25, or povidone K17.

[0012] In some embodiments, the first binder is povidone K30.

[0013] In some embodiments, the second binder is PEG-2000, PEG-3000, or PEG-4000.

[0014] In some embodiments, the second binder is PEG-4000.

[0015] In some embodiments, the disintegrant is selected from one or more of sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, and cross-linked carboxymethyl cellulose.

[0016] In some embodiments, the disintegrant is croscarmellose sodium.

[0017] In some embodiments, the lubricant is selected from one or more of talc, calcium stearate, zinc stearate, stearic acid, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, and sodium stearyl fumarate.

[0018] In some embodiments, the lubricant is magnesium stearate.

[0019] In some embodiments, the tablet comprises the following components by weight: 70-75% oxcarbazepine, 15-20% microcrystalline cellulose, 1.8-2.3% povidone, 0.5-1% polyethylene glycol, 5-7% croscarmellose sodium, and 1.0% magnesium stearate.

[0020] In some embodiments, the tablet comprises the following components by weight: 73.5% oxcarbazepine, 17.0% microcrystalline cellulose, 2.0% povidone, 0.8% polyethylene glycol, 5.7% croscarmellose sodium, and 1.0% magnesium stearate.

[0021] In some embodiments, the tablet comprises the following components by weight: 73.5% oxcarbazepine, 17.0% microcrystalline cellulose, 2.0% povidone K30, 0.8% PEG-4000, 5.7% croscarmellose sodium, and 1.0% magnesium stearate.

[0022] In some embodiments, the tablet further comprises a coating material, wherein the coating material increases the weight of the tablet by 3-5%, where the total weight of the tablet is the sum of the weights of the oxcarbazepine, the first binder, the second binder, the filler, the disintegrant, and the lubricant. For example, the weight increase is 3%, 3.5%, 4%, 4.5%, or 5%. The coating material is selected from one or more gastric-soluble film coatings.

[0023] In some embodiments, the coating material is Opadry.

[0024] The present invention also provides a method for preparing the above-mentioned oxcarbazepine tablets, comprising the following steps:

[0025] (1) Micronization: Oxcarbazepine is micronized to a particle size of D90 ≤ 30 μm and D50 ≤ 10 μm;

[0026] (2) Wet granulation: Add the prescribed amount of micronized oxcarbazepine, the first binder, the second binder, and a portion of the prescribed amount of filler to a high shear wet granulator. Turn on stirring and shearing, mix until uniform, and add an appropriate amount of purified water to the granulator using a spray gun to granulate.

[0027] (3) Granulation: drying and granulating the wet granules obtained in step (2);

[0028] (4) Total mixing: the dry whole granules obtained in step (3) above are mixed evenly with the prescribed amount of disintegrant and another portion of filler, and then the prescribed amount of lubricant is added and further mixed evenly to obtain the total mixed granules;

[0029] (5) tableting: tableting the mixed granules obtained in step (4) to obtain plain tablets;

[0030] (6) Coating: The plain tablets are coated with a gastric soluble film coating.

[0031] In some embodiments, the filler in step (2) accounts for 2 / 3 of the prescription amount.

[0032] In some embodiments, the amount of purified water added in step (2) accounts for 14-20% of the weight of the granulation dry powder.

[0033] In some embodiments, the amount of purified water added in step (2) accounts for 17% of the weight of the granulation dry powder.

[0034] In some embodiments, the coating in step (6) increases in weight by 3-5%; the coating material is selected from one or more gastric-soluble film coatings.

[0035] In some embodiments, the preparation method comprises the following steps:

[0036] (1) Micronization: Oxcarbazepine is micronized to a particle size of D90 ≤ 30 μm and D50 ≤ 10 μm;

[0037] (2) Wet granulation: Add the prescribed amount of micronized oxcarbazepine, povidone K30, PEG-4000, and 2 / 3 of the prescribed amount of microcrystalline cellulose to a high shear wet granulator. Turn on stirring and shearing, mix until uniform, and add an appropriate amount of purified water to the granulator using a spray gun to granulate. The amount of purified water added is 17% of the weight of the granulation dry powder.

[0038] (3) Granulation: drying and granulating the wet granules obtained in step (2);

[0039] (4) Total mixing: the dry whole granules obtained in step (3) above are mixed evenly with the prescribed amount of cross-linked sodium carboxymethyl cellulose and the remaining portion of microcrystalline cellulose, and then the prescribed amount of magnesium stearate is added and further mixed evenly to obtain the total mixed granules;

[0040] (5) tableting: tableting the mixed granules obtained in step (4) to obtain plain tablets;

[0041] (6) Coating: Use Opadry coating to increase the weight of the plain tablets by 3-5%.

[0042] Compared with the prior art, the present invention has the following advantages: 1. No specific flow-aiding excipients, such as colloidal silicon dioxide, need to be added to the formulation, thereby avoiding the harm of flow-aid dust to workers; 2. The formulation uses a combination of povidone and polyethylene glycol adhesives, and combines the selection of the types and amounts of other excipients to improve the fluidity of the total mixed particles in the formulation, ensuring smooth material discharge during the tableting process and meeting the needs of large-scale tableting production. DETAILED DESCRIPTION

[0043] In order to better understand the technical solution of the present invention, the technical solution of the present invention is further described below in conjunction with specific embodiments. The embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0044] Example 1

[0045]

[0046]

[0047] Preparation method:

[0048] (1) Micronization: Oxcarbazepine is micronized to a particle size of D90 ≤ 30 μm and D50 ≤ 10 μm;

[0049] (2) Wet granulation: Add the prescribed amount of micronized oxcarbazepine, povidone K30, PEG-4000, and 2 / 3 of the prescribed amount of microcrystalline cellulose to a high shear wet granulator. Turn on stirring and shearing, mix until uniform, and add an appropriate amount of purified water to the granulator using a spray gun to granulate. The amount of purified water added is 17% of the weight of the granulation dry powder.

[0050] (3) Granulation: The wet granules obtained in step (2) are dried until the loss on density (LOD) of the granules is less than 1.0%, and the dried granules are granulated using a sieve with an aperture of 1.2 mm.

[0051] (4) Total mixing: the dry whole granules obtained in step (3) above are mixed evenly with the prescribed amount of cross-linked sodium carboxymethyl cellulose and the remaining portion of microcrystalline cellulose, and then the prescribed amount of magnesium stearate is added and further mixed evenly to obtain the total mixed granules;

[0052] (5) tableting: tableting the mixed granules obtained in step (4) to obtain plain tablets;

[0053] (6) Coating: Use Opadry coating material to coat the plain tablets to increase the weight by 3%.

[0054] Example 2

[0055]

[0056] In Example 2, oxcarbazepine tablets were prepared using the method described in Example 1.

[0057] Example 3

[0058]

[0059] In Example 3, oxcarbazepine tablets were prepared using the method described in Example 1.

[0060] Comparative Example 1

[0061]

[0062] In Comparative Example 1, oxcarbazepine tablets were prepared using the method described in Example 1, with only povidone K30 used as the binder, and no PEG-4000 was used.

[0063] Comparative Example 2

[0064]

[0065]

[0066] In Comparative Example 2, oxcarbazepine tablets were prepared using the method described in Example 1, except that only PEG-4000 was used as the binder, without using povidone K30.

[0067] Comparative Example 3

[0068]

[0069] In Comparative Example 3, oxcarbazepine tablets were prepared using the method described in Example 1, and the binders were hypromellose 603 and PEG-4000.

[0070] Comparative Example 4

[0071]

[0072]

[0073] In Comparative Example 4, oxcarbazepine tablets were prepared using the method described in Example 1, with the binders being povidone and PEG-6000.

[0074] Comparative Example 5

[0075]

[0076] In Comparative Example 5, oxcarbazepine tablets were prepared using the method described in Example 1, and the mass ratio of the filler microcrystalline cellulose added to the inner and outer portions was 1:1.

[0077] Comparative Example 6

[0078]

[0079] In Comparative Example 6, oxcarbazepine tablets were prepared using the method described in Example 1, and the mass ratio of the filler microcrystalline cellulose added to the inner and outer portions was 3:1.

[0080] Comparative Example 7

[0081]

[0082] (1) Micronization: Oxcarbazepine is micronized to a particle size of D90 ≤ 30 μm and D50 ≤ 10 μm;

[0083] (2) Wet granulation: Add the prescribed amount of micronized oxcarbazepine, hypromellose, and 2 / 3 of the prescribed amount of microcrystalline cellulose to a high shear wet granulator. Turn on stirring and shearing, mix until uniform, and add an appropriate amount of purified water to the granulator using a spray gun to granulate. The amount of purified water added is 17% of the weight of the granulation dry powder.

[0084] (3) Granulation: The wet granules obtained in step (2) are dried until the loss on density (LOD) of the granules is less than 1.0%, and the dried granules are granulated using a sieve with an aperture of 1.2 mm.

[0085] (4) Total mixing: the dry whole granules obtained in step (3) above are mixed evenly with the prescribed amount of crospovidone, colloidal silicon dioxide and the remaining part of microcrystalline cellulose, and then the prescribed amount of magnesium stearate is added and further mixed evenly to obtain the total mixed granules;

[0086] (5) tableting: tableting the mixed granules obtained in step (4) to obtain plain tablets;

[0087] (6) Coating: Use Opadry coating material to coat the plain tablets to increase the weight by 3%.

[0088] Comparative Example 8

[0089]

[0090]

[0091] In Comparative Example 8, oxcarbazepine tablets were prepared using the method described in Example 1.

[0092] Comparative Example 9

[0093]

[0094] In Comparative Example 9, oxcarbazepine tablets were prepared using the method described in Example 1.

[0095] Product quality testing methods:

[0096] 1. The dissolution test method of oxcarbazepine tablets of the present invention: The measurement conditions refer to the dissolution curve determination conditions of oxcarbazepine tablets recommended by the US FDA: 600 mg specification, 900 mL of 1% SDS solution, 60 rpm, paddle method.

[0097] 2. The content of oxcarbazepine tablets described in the present invention is determined by high performance liquid chromatography (General Rule 0512) in the dark.

[0098] Test solution: Take 20 tablets of this product, accurately weigh, grind, accurately weigh an appropriate amount (equivalent to 275 mg of oxcarbazepine), place it in a 250 mL volumetric flask, add an appropriate amount of mobile phase, sonicate to dissolve oxcarbazepine, dilute to the scale with mobile phase, shake well, filter, and take the filtrate.

[0099] Reference solution: accurately weigh the oxcarbazepine reference substance, dissolve it in the mobile phase, and quantitatively dilute it to a solution containing approximately 0.11 mg per 1 mL.

[0100] Chromatographic conditions: octadecylsilane bonded silica gel was used as the filler; the mobile phase was a buffer solution (accurately weigh 6.8 g of potassium dihydrogen phosphate dissolved in 1000 ml of water, 2 mL of triethylamine was added, and the pH was adjusted to 6.0 ± 0.1 with phosphoric acid)-methanol-acetonitrile (64:20:16); the detection wavelength was 215 nm; the injection volume was 10 μL.

[0101] 3. Impurity testing method for the oxcarbazepine tablets of the present invention: Determine according to the high performance liquid chromatography method (General Rule 0512), test in the dark, and prepare freshly before use;

[0102] Test solution: Take 20 tablets of this product, accurately weigh, grind, accurately weigh an appropriate amount (equivalent to 50 mg of oxcarbazepine), place it in a 50 mL volumetric flask, add an appropriate amount of acetonitrile, sonicate to dissolve the oxcarbazepine, dilute to the scale with 1.8 mg / mL ascorbic acid solution, shake well, centrifuge, and take the supernatant.

[0103] Control solution a: Dissolve the oxcarbazepine impurity mixed reference substance in 0.5 mL of acetonitrile solution and dilute to 1 mL with 1.8 mg / mL ascorbic acid solution.

[0104] Control solution b: Transfer 1 mL of the test solution to a 100 mL brown volumetric flask and dilute to the mark with diluent (acetonitrile: 1.8 mg / mL ascorbic acid solution = 50:50). Then accurately transfer 1 mL to a 10 mL brown volumetric flask and dilute to the mark with diluent.

[0105] Chromatographic conditions: phenylhexyl silica gel was used as the filler; the mobile phase was a buffer solution (accurately weigh 6.8 g of potassium dihydrogen phosphate dissolved in 1000 mL of water, 2 mL of triethylamine was added, and the pH was adjusted to 6.0±0.1 with phosphoric acid)-methanol-acetonitrile (64:20:16); the detection wavelength was 240 nm; the injection volume was 10 μL.

[0106] 4. The angle of repose of the mixed granules before tableting described in the present invention is primarily used to evaluate flowability. This angle of repose is measured according to the "Guiding Principles for Determination of Powder Flowability" (Draft for Comment) issued by the Chinese Pharmacopoeia Commission. The angle of repose is determined by slowly adding granules from the top of a funnel. The angle of repose is the angle at which the conical accumulation of material leaking from the bottom of the funnel forms a horizontal surface. An angle of repose below 40° indicates satisfactory flowability, while an angle above 40° indicates poor flowability. A smaller angle of repose indicates better flowability.

[0107] Test Example 1

[0108] The quality of the oxcarbazepine tablets prepared in Examples 1-3 and Comparative Examples 1-9 was checked, and the results were as follows:

[0109] Table 1

[0110]

[0111] From the results in Table 1, it can be seen that the oxcarbazepine tablets prepared in Examples 1-3 and Comparative Examples 1-9 are all off-white in color and have no sticking problem during tableting. However, the tablets of Comparative Examples 2 and 9 loosened and split during tableting.

[0112] In Comparative Example 2, only PEG-4000 was used as the binder, resulting in insufficient granular viscosity, weak intergranular bonding, and easy breakage during tableting. In Comparative Example 9, the proportion of povidone K30 in the binder was too low (1.6%), while the proportion of PEG-4000 was too high (1.2%), which also had the problem of insufficient granular viscosity, resulting in tablet splitting during tableting.

[0113] Test Example 2

[0114] The dissolution performance of the oxcarbazepine tablets prepared in Examples 1-3 and Comparative Examples 1 and 3-8 and the reference preparation (Novartrile 600 mg) was tested. The cumulative dissolution rate (%) of the oxcarbazepine tablets at 10 min, 15 min, 20 min, 30 min, 45 min, 60 min, 90 min, and 135 min was as follows:

[0115] Table 2

[0116]

[0117] From the results in Table 2, it can be seen that there is no significant difference in the dissolution rate between the oxcarbazepine tablets prepared in Examples 1-3 and Comparative Examples 3-7 and the reference preparation, and the oxcarbazepine tablets prepared in Comparative Examples 1 and 8 dissolve more slowly than the reference preparation.

[0118] Excessive use of povidone K30 may result in an overly dense particle structure, slowing dissolution. The hydrophilicity of PEG-4000 accelerates water penetration into the tablet, promoting the effectiveness of the disintegrant (croscarmellose sodium), thereby improving tablet dissolution performance. Comparative Example 1 did not use PEG-4000, and in Comparative Example 7, too little PEG-4000 was used, resulting in decreased particle disintegration and slower dissolution.

[0119] Test Example 3

[0120] The angle of repose of the mixed granules of Examples 1-3 and Comparative Examples 3-7 before tableting was measured and calculated. The results are shown in Table 3:

[0121] Table 3

[0122]

[0123] From the results in Table 3, it can be seen that the fluidity of the mixed granules before tableting in Comparative Examples 3-7 is poor; the fluidity of the mixed granules before tableting prepared in Examples 1-3 is good, especially the fluidity of the mixed granules before tableting prepared in Example 2 is better.

[0124] The adhesive povidone K30 and PEG-4000 combine to form a uniform particle surface in wet granulation, reduce the proportion of fine powder, and thus improve fluidity. In the embodiment, the filler microcrystalline cellulose adopts an internal and external addition ratio of 2: 1 to optimize the particle size distribution and reduce the friction between particles. However, Comparative Example 3 uses hypromellose instead of povidone, which may increase the flow resistance due to the poor film-forming property of the adhesive and the rough surface of the particles. Comparative Example 4 uses PEG-6000 instead of PEG-4000, and the resulting total mixed particles have a rough surface, more fine powder, and poor fluidity. Although Comparative Example 7 adds colloidal silicon dioxide as a glidant, the angle of repose is still as high as 46.42°, indicating that its fluidity improvement is limited and there is a risk of dust hazard.

[0125] The combination of povidone K30 and PEG-4000 can avoid the use of colloidal silicon dioxide, thus ensuring fluidity while avoiding dust hazards.

[0126] Test Example 4

[0127] The oxcarbazepine tablets prepared in Examples 1-3 and the reference preparation were placed at a temperature of 40°C ± 2°C and a humidity of 75% RH ± 5% RH for 6 months. The samples were measured at 0 days and 6 months to determine the oxcarbazepine content and total impurity content. The results are as follows:

[0128] Table 4

[0129]

[0130] As can be seen from the results in Table 4, the oxcarbazepine tablets prepared in Examples 1-3 had controllable growth of total impurities during the acceleration period, and the content of the main component did not decrease significantly, showing good stability. In addition, there was no significant difference in total impurities or oxcarbazepine content compared with the reference preparation, showing stability comparable to that of the reference preparation.

[0131] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that it is still possible to modify the technical solutions described in the aforementioned embodiments, or to make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. An oxcarbazepine tablet, characterized in that The tablet comprises the following components in weight percentage: 70-75% oxcarbazepine, 15-20% filler, 1.8-2.3% first binder, 0.5-1% second binder, 5-7% disintegrant, and 0.8-1.2% lubricant; wherein the first binder is selected from povidone; and the second binder is selected from polyethylene glycol.

2. The tablet according to claim 1, characterized in that The filler is selected from one or more of lactose, sucrose, starch, pregelatinized starch, dextrin, mannitol, sorbitol, and microcrystalline cellulose; preferably microcrystalline cellulose.

3. The tablet according to claim 1, characterized in that The first adhesive is povidone K30.

4. The tablet according to claim 1, characterized in that The second adhesive is PEG-4000.

5. The tablet according to claim 1, characterized in that The disintegrant is selected from one or more of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, and cross-linked carboxymethyl cellulose; preferably cross-linked sodium carboxymethyl cellulose.

6. The tablet according to claim 1, characterized in that The lubricant is selected from one or more of talc, calcium stearate, zinc stearate, stearic acid, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, and sodium stearyl fumarate; preferably magnesium stearate.

7. The tablet according to claim 1, characterized in that The tablet comprises the following components in weight percentage: 73.5% oxcarbazepine, 17.0% microcrystalline cellulose, 2.0% povidone, 0.8% polyethylene glycol, 5.7% cross-linked carboxymethyl cellulose sodium, and 1.0% magnesium stearate.

8. The tablet according to claim 1, wherein The tablet further comprises a coating material, wherein the coating material is selected from one or more gastric soluble film coatings, preferably Opadry.

9. The method for preparing the oxcarbazepine tablet according to any one of claims 1 to 8, characterized in that: The preparation method comprises the following steps: (1) Micronization: Oxcarbazepine is micronized to a particle size of D90 ≤ 30 μm and D50 ≤ 10 μm; (2) Wet granulation: Add the prescribed amount of micronized oxcarbazepine, the first binder, the second binder, and a portion of the prescribed amount of filler to a high shear wet granulator. Turn on stirring and shearing, mix until uniform, and add an appropriate amount of purified water to the granulator using a spray gun to granulate. (3) Granulation: drying and granulating the wet granules obtained in step (2); (4) Total mixing: the dry whole granules obtained in step (3) above are mixed evenly with the prescribed amount of disintegrant and another portion of filler, and then the prescribed amount of lubricant is added and further mixed evenly to obtain the total mixed granules; (5) tableting: tableting the mixed granules obtained in step (4) to obtain plain tablets; (6) Coating: The plain tablets are coated with a gastric soluble film coating.

10. The preparation method according to claim 9, characterized in that The amount of purified water added in step (2) is 14-20% of the weight of the granulation dry powder, preferably 17%.

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