Lamotrigine tablet and preparation method thereof

Abstract

The invention discloses a lamotrigine tablet and a preparation method thereof. The lamotrigine tablet is prepared from the following raw materials in parts by mass: 45 to 55 parts of lamotrigine, 45 to 55 parts of lactose, 45 to 55 parts of microcrystalline cellulose, 4.5 to 5.5 parts of carboxymethyl starch sodium, 4.5 to 5.5 parts of povidone K30, 0.36 to 0.44 part of yellow iron oxide and 0.72 to 0.88 part of magnesium stearate. A fluidized bed is adopted, part of raw materials and auxiliary materials are subjected to wet granulation by using povidone K30, after proper drying, carboxymethyl starch sodium and magnesium stearate are added, and the mixture is uniformly mixed and tableted. By adopting a wet granulation process, the granules prepared by the process are good in flowability and compressibility, the drug property is stable, the production process is simple, and industrial production is facilitated.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a lamotrigine tablet and a preparation method thereof. Background Art

[0002] Lamotrigine, chemical name: 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, molecular formula C9H7Cl2N5, molecular weight 256.09, chemical structural formula:

[0003] Lamotrigine is a phenyltriazine anti-epileptic drug. Lamotrigine mainly acts on voltage-dependent sodium channels, inhibits repeated discharges, and also acts on glutamate-related neurotransmitters. It can inhibit glutamate and aspartic acid, and can stabilize the presynaptic membrane and inhibit the release of glutamate and aspartic acid. It is mainly used for the treatment of intractable epilepsy.

[0004] At present, there are various lamotrigine preparations on the global market, including ordinary tablets, sustained-release tablets, orally disintegrating tablets, and dispersible tablets. Existing tablets still have certain defects, such as poor storage performance and slow release rate. Therefore, it is necessary to provide a lamotrigine tablet with stable properties and fast release rate.

[0005] The information disclosed in this background art section is only intended to enhance the overall understanding of the present invention and should not be regarded as an admission or any form of implication that this information constitutes prior art already known to those of ordinary skill in the art. Summary of the Invention

[0006] The purpose of the present invention is to provide a lamotrigine tablet and a preparation method thereof. The preparation method is rapid and simple, the granules have good fluidity and compressibility, the quality is qualified, the properties are stable, the production time can be greatly shortened, and it is convenient for large-scale production.

[0007] To achieve the above purpose, the technical solution provided by a specific embodiment of the present invention is as follows:

[0008] A lamotrigine tablet, comprising the following raw materials in parts by mass: 45-55 parts of lamotrigine, 45-55 parts of lactose, 45-55 parts of microcrystalline cellulose, 4.5-5.5 parts of sodium carboxymethyl starch, 4.5-5.5 parts of polyvinylpyrrolidone K30, 0.36-0.44 parts of yellow ferric oxide, and 0.72-0.88 parts of magnesium stearate.

[0009] In one or more embodiments of the present invention, the weight ratio of lamotrigine, lactose, and microcrystalline cellulose is 1:(0.96-1.04):(0.96-1.04).

[0010] In one or more embodiments of the present invention, the weight ratio of lamotrigine, sodium carboxymethyl starch, and povidone K30 is 10:(0.96 - 1.04):(0.96 - 1.04).

[0011] In one or more embodiments of the present invention, the D90 particle size of lamotrigine is 25 μm ± 5 μm.

[0012] The technical solution provided by another specific embodiment of the present invention is as follows:

[0013] A method for preparing lamotrigine tablets, comprising the following steps:

[0014] Prepare raw materials of lamotrigine, lactose, microcrystalline cellulose, sodium carboxymethyl starch, povidone K30, yellow ferric oxide, and magnesium stearate;

[0015] Mix lamotrigine, lactose, yellow ferric oxide, and microcrystalline cellulose to form a mixed powder;

[0016] Mix povidone K30 and water to form a binder;

[0017] Mix the mixed powder and a part of sodium carboxymethyl starch, and then add the binder to form a soft material;

[0018] Perform wet granulation, drying, and dry granulation on the soft material to obtain dry granules;

[0019] Mix the dry granules, magnesium stearate, and the remaining sodium carboxymethyl starch, and press tablets.

[0020] In one or more embodiments of the present invention, when the mixed powder is mixed with a part of sodium carboxymethyl starch, the mass of the sodium carboxymethyl starch used is 45% - 50% of the total mass of the raw material sodium carboxymethyl starch.

[0021] In one or more embodiments of the present invention, when the mixed powder is mixed with a part of sodium carboxymethyl starch, the stirring frequency is 18 - 22 Hz, the chopping frequency is 25 - 30 Hz, and the time is 20 - 30 min.

[0022] In one or more embodiments of the present invention, the drying operation is to dry at 60°C - 70°C until the water content is 1% - 3.5%.

[0023] In one or more embodiments of the present invention, when the dry granules, magnesium stearate, and the remaining sodium carboxymethyl starch are mixed, the rotation speed is 10 r / min - 20 r / min, and the time is 8 - 15 min.

[0024] In one or more embodiments of the present invention, the wet granulation is performed using a 18 - mesh to 24 - mesh sieve for granulation, and / or the dry granulation is performed using a 20 - mesh to 26 - mesh sieve for granulation.

[0025] Compared with the prior art, after adding sodium carboxymethyl starch in batches in the present invention, the granules have good fluidity and compressibility, and the production cycle is significantly shortened. By controlling the particle size of lamotrigine and the ratio of lamotrigine, lactose and microcrystalline cellulose, the quality of the drug is qualified, the properties are stable, and the contents of various impurities remain basically unchanged during the storage validity period. By increasing the dosage of yellow ferric oxide, the antioxidant property of the drug is increased. By controlling the ratio of sodium carboxymethyl starch and polyvinylpyrrolidone K30, the tablets produced have a fast release rate, high solubility and dissolution rate in different pH environments, which are consistent with the reference preparation. Detailed implementation mode

[0026] In order to enable those skilled in the art to better understand the technical solutions in the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative efforts shall fall within the protection scope of the present invention.

[0027] A specific implementation mode of the present invention provides a lamotrigine tablet, which comprises the following raw materials in parts by mass: 45-55 parts of lamotrigine, 45-55 parts of lactose, 45-55 parts of microcrystalline cellulose, 4.5-5.5 parts of sodium carboxymethyl starch, 4.5-5.5 parts of polyvinylpyrrolidone K30, 0.36-0.44 parts of yellow ferric oxide, and 0.72-0.88 parts of magnesium stearate.

[0028] Specifically, lactose helps to increase the tablet volume and improve compressibility. Lactose has good water solubility, can promote tablet disintegration, and its sweetness can also improve the tablet taste. Microcrystalline cellulose can not only increase the tablet volume and maintain the tablet shape, but also improve the structural stability of the tablet with its adhesiveness. In addition, it can absorb water and expand, which can promote tablet disintegration. Sodium carboxymethyl starch can effectively improve the disintegration speed of tablets and the dissolution rate of lamotrigine. Polyvinylpyrrolidone K30 can effectively bind the raw materials, improve compressibility, and also has a certain promoting effect on tablet disintegration. Yellow ferric oxide can improve the antioxidant property of tablets. Its chemical properties are stable and it is not easy to react with drugs, which can improve the stability of tablets. Magnesium stearate can improve the fluidity of raw materials, help to improve the mixing uniformity of raw materials and the filling property in the mold during tableting, and improve compressibility.

[0029] Furthermore, the weight ratio of lamotrigine, lactose and microcrystalline cellulose is 1:(0.96 - 1.04):(0.96 - 1.04), preferably 1:1:1; the weight ratio of lamotrigine, sodium carboxymethyl starch and povidone K30 is 10:(0.96 - 1.04):(0.96 - 1.04), preferably 10:1:1. The above weight ratios are preferred ratios, which can make the tablets qualified in quality and stable in nature, and the contents of various impurities in the tablets remain basically unchanged during the storage period of validity.

[0030] Furthermore, the D90 particle size of lamotrigine is 25 μm ± 5 μm.

[0031] Specifically, by controlling the particle size, the dissolution rate of lamotrigine can be increased, and at the same time, the process is stable.

[0032] Another specific embodiment of the present invention provides a preparation method of lamotrigine, which includes steps 1 - 6.

[0033] Step 1, prepare raw materials including lamotrigine, lactose, microcrystalline cellulose, sodium carboxymethyl starch, povidone K30, yellow ferric oxide and magnesium stearate.

[0034] Specifically, prepare the above raw materials according to the raw material ratio.

[0035] Step 2, mix lamotrigine, lactose, yellow ferric oxide and microcrystalline cellulose to form a mixed powder.

[0036] Specifically, mix lamotrigine, lactose, yellow ferric oxide and microcrystalline cellulose, and pass through a 40 - mesh sieve to obtain a mixed powder.

[0037] Step 3, mix povidone K30 and water to form a binder.

[0038] Specifically, the amount of water used is 10 times the mass of povidone K30. Add povidone K30 to water and stir until completely dissolved to obtain a binder.

[0039] Step 4, mix the mixed powder and a part of sodium carboxymethyl starch, and then add the binder to form a soft material.

[0040] Specifically, in this step, the mass of sodium carboxymethyl starch used is 45% - 50% of the total mass of the raw material sodium carboxymethyl starch. The mixed powder and a part of sodium carboxymethyl starch are mixed in a wet granulator, the stirring frequency is 18 - 22 Hz, the chopping frequency is 25 - 30 Hz, and the time is 20 - 30 min. After adding the binder, stop stirring, and then start the equipment to run for 3 min to obtain a soft material.

[0041] Step 5, perform wet screening, drying and dry screening on the soft material to obtain dry granules.

[0042] Specifically, wet granulation is carried out by screening with a 18-mesh to 24-mesh sieve, drying is carried out at 60°C - 70°C until the water content is 1% - 3.5%, and dry granulation is carried out by screening with a 20-mesh to 26-mesh sieve.

[0043] Step 6, mix the dry granules, magnesium stearate and the remaining sodium carboxymethyl starch, and press tablets.

[0044] Specifically, mix at a rotation speed of 10 r / min - 20 r / min for 8 - 15 min and then press tablets. In Steps 4 and 6, the sodium carboxymethyl starch is mixed in two times, which can ensure good flowability of the material during total mixing, and at the same time improve the compressibility of the material and the viscosity of the granules.

[0045] The present invention will be further described in detail below in conjunction with specific embodiments.

[0046] Example 1

[0047] A lamotrigine tablet, in parts by weight, the raw materials include 45 parts of lamotrigine, 45 parts of lactose, 45 parts of microcrystalline cellulose, 4.5 parts of sodium carboxymethyl starch, 4.5 parts of polyvinylpyrrolidone K30, 0.36 part of yellow ferric oxide and 0.72 part of magnesium stearate.

[0048] Preparation process: Weigh lamotrigine, yellow ferric oxide, lactose and microcrystalline cellulose according to the prescription amount, add them to a swing granulator, and obtain a mixed powder after passing through a 40-mesh stainless steel sieve; weigh polyvinylpyrrolidone K30 and half of the total amount of sodium carboxymethyl starch; add polyvinylpyrrolidone K30 to purified water and stir until completely dissolved to obtain an adhesive aqueous solution.

[0049] Add the mixed powder and half of the total amount of sodium carboxymethyl starch to a wet granulator in turn, set the stirring frequency to 20 Hz, the chopping frequency to 30 Hz, turn on the stirring and cutter to start the equipment and run for 25 min. Set the stirring frequency to 20 Hz and the chopping frequency to 25 Hz, quickly add the adhesive, and immediately stop stirring after adding; start the equipment and run for 3 min to obtain soft materials.

[0050] Place the soft materials in a swing granulator equipped with a 20-mesh stainless steel sieve for wet granulation; place the wet granules in a multi-functional fluidized bed granulator for drying, set the inlet air temperature to 65°C and the fan frequency to 20 Hz for drying. After drying for 10 min, obtain dry granules; place the dry granules in a swing granulator equipped with a 24-mesh stainless steel sieve for dry granulation.

[0051] Place the dry granulated particles, magnesium stearate and the remaining sodium carboxymethyl starch in a hoist mixer, set the mixing rotation speed to 15 r / min and the mixing time to 10 min, mix to obtain intermediate particles; press the intermediate particles according to the tablet specifications.

[0052] Example 2

[0053] A lamotrigine tablet, calculated by weight parts, the raw materials include 50 parts of lamotrigine, 50 parts of lactose, 50 parts of microcrystalline cellulose, 5 parts of sodium carboxymethyl starch, 5 parts of polyvinylpyrrolidone K30, 0.40 part of yellow ferric oxide, and 0.80 part of magnesium stearate.

[0054] Preparation process: Weigh lamotrigine, yellow ferric oxide, lactose, and microcrystalline cellulose according to the prescription amount, add them to a rocking granulator, and obtain a mixed powder after passing through a 20-mesh stainless steel sieve; Weigh polyvinylpyrrolidone K30 and half of the total amount of sodium carboxymethyl starch; Add polyvinylpyrrolidone K30 to purified water and stir until completely dissolved to obtain an adhesive aqueous solution.

[0055] Add the mixed powder and half of the total amount of sodium carboxymethyl starch to a wet granulating mixer in sequence, set the stirring frequency at 20 Hz, the chopping frequency at 25 Hz, turn on the stirring and cutter to start the equipment and run for 25 min; Quickly add the adhesive, and immediately stop stirring after adding; The equipment continues to run for 3 min to obtain soft materials.

[0056] Place the soft materials in a rocking granulator equipped with a 20-mesh stainless steel sieve for wet granulation; Place the wet granules in a multi-functional fluidized bed granulating and coating machine for drying, set the inlet air temperature at 60 °C, and the fan frequency at 30 Hz for drying. After drying for 5 min, obtain dried granules; Place the dried granules in a rocking granulator equipped with a 20-mesh stainless steel sieve for dry granulation.

[0057] Place the dry granulated particles, magnesium stearate, and the remaining sodium carboxymethyl starch in a hoist mixer, set the mixing rotation speed at 15 r / min, and the mixing time at 5 min to mix and obtain intermediate particles; Press the intermediate particles according to the tablet specifications.

[0058] Example 3

[0059] A lamotrigine tablet, calculated by weight parts, the raw materials include 55 parts of lamotrigine, 55 parts of lactose, 55 parts of microcrystalline cellulose, 5.5 parts of sodium carboxymethyl starch, 5.5 parts of polyvinylpyrrolidone K30, 0.44 part of yellow ferric oxide, and 0.88 part of magnesium stearate.

[0060] Preparation process: Weigh lamotrigine, yellow ferric oxide, lactose, and microcrystalline cellulose according to the prescription amount, add them to a rocking granulator, and obtain a mixed powder after passing through a 40-mesh stainless steel sieve; Weigh polyvinylpyrrolidone K30 and half of the total amount of sodium carboxymethyl starch; Add polyvinylpyrrolidone K30 to purified water and stir until completely dissolved to obtain an adhesive aqueous solution.

[0061] Add the mixed powder and half of the total amount of sodium carboxymethyl starch into the wet granulator in sequence, set the stirring frequency at 20 Hz, the chopping frequency at 30 Hz, start stirring and the cutter to run the equipment for 15 min; quickly add the binder, and immediately stop stirring after adding; continue to run the equipment for 3 min to obtain the soft material.

[0062] Place the soft material in a swing granulator equipped with a 20-mesh stainless steel screen for wet sizing; place the wet granules in a multi-functional fluidized bed granulator for drying, set the inlet air temperature at 65 °C, and the fan frequency at 40 Hz for drying. After drying for 3 min, obtain the dried granules; place the dried granules in a swing granulator equipped with a 24-mesh stainless steel screen for dry sizing.

[0063] Place the dry-sized granules, magnesium stearate and the remaining sodium carboxymethyl starch in a hoist mixer, set the mixing rotation speed at 20 r / min, and the mixing time at 5 min to mix and obtain the intermediate granules; press the intermediate granules according to the tablet specifications.

[0064] Example 4

[0065] The difference between this example and Example 1 is that, by weight, the raw materials include 45 parts of lamotrigine, 43.2 parts of lactose, 46.8 parts of microcrystalline cellulose, 4.32 parts of sodium carboxymethyl starch, 4.68 parts of polyvinylpyrrolidone K30, 0.36 part of yellow ferric oxide, and 0.72 part of magnesium stearate.

[0066] Example 5

[0067] The difference between this example and Example 1 is that, by weight, the raw materials include 45 parts of lamotrigine, 46.8 parts of lactose, 43.2 parts of microcrystalline cellulose, 4.68 parts of sodium carboxymethyl starch, 4.32 parts of polyvinylpyrrolidone K30, 0.36 part of yellow ferric oxide, and 0.72 part of magnesium stearate.

[0068] Comparative Example 1

[0069] The difference between this comparative example and Example 1 is that the particle size of lamotrigine is 40 μm.

[0070] Comparative Example 2

[0071] The difference between this comparative example and Example 1 is that, by weight, the raw materials include 45 parts of lamotrigine, 40 parts of lactose, 35 parts of microcrystalline cellulose, 4.5 parts of sodium carboxymethyl starch, 4.5 parts of polyvinylpyrrolidone K30, 0.36 part of yellow ferric oxide, and 0.72 part of magnesium stearate.

[0072] Comparative Example 3

[0073] The difference between this comparative example and Example 1 is that, by weight, the raw materials include 45 parts of lamotrigine, 45 parts of lactose, 45 parts of microcrystalline cellulose, 3.0 parts of sodium carboxymethyl starch, 2.5 parts of polyvinylpyrrolidone K30, 0.36 part of yellow iron oxide, and 0.72 part of magnesium stearate.

[0074] Measure the mass contents of impurity A (3-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-5(4H)-one), impurity B ((2E)-[2-(diaminomethylene)diazenylidene](2,3-dichlorophenyl)acetonitrile), impurity C ((2Z)-[2(diaminomethylene)diazenylidene](2,3-dichlorophenyl)acetonitrile), impurity E (2,3-dichlorobenzoic acid), impurity F (N-[5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3]-2,3-dichlorobenzamide), and impurity G (6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine) in the lamotrigine tablets of Examples 1-3, and test the dissolution in pH 6.8 phosphate buffer solution. Then store the lamotrigine tablets for 24 months, and measure the impurity content and dissolution again. The results are shown in Table 1 and Table 2.

[0075] Table 1 Quality comparison of lamotrigine tablets when stored for 0 months

[0076]

[0077] Table 2 Quality comparison of lamotrigine tablets when stored for 24 months

[0078]

[0079] As can be seen from Table 1 and Table 2, the lamotrigine tablets in the examples of the present invention have stable properties, and the impurity content remains basically unchanged within 24 months of storage. Moreover, the lamotrigine tablets in Examples 4 and 5 also show relatively stable properties, and the impurity content remains basically unchanged within 24 months of storage. In addition, after storage for 24 months, the impurity content of Comparative Examples 1-3 increased significantly, indicating that only the products obtained by referring to the lamotrigine particle size and raw material ratio disclosed in the present invention have excellent stability.

[0080] Select the reference preparation of lamotrigine tablets (license holder The Wellcome Foundation Limited), and the specific specifications include 50 mg (batch numbers F64J, F88X, V57V) and 25 mg (batch numbers 3C7C, EJ3M, PW5R), and compare with the lamotrigine tablets prepared in the examples to detect the dissolution in different pH environments.

[0081] Table 3 Dissolution results in pH 1.0 hydrochloric acid at 50 r / min

[0082]

[0083]

[0084] Table 4 Dissolution Results in pH 6.8 Phosphate Buffer at 50 rpm

[0085]

[0086]

[0087] Table 5 Dissolution Results in pH 4.5 Phosphate Buffer at 50 rpm

[0088]

[0089]

[0090] Table 6 Dissolution Results in Water at 50 rpm

[0091]

[0092]

[0093] As can be seen from Tables 3 - 6, the tablets in the examples have high solubility and dissolution in water and different pH environments, which are consistent with the reference preparation. In addition, the tablets in the comparative examples were tested and found to have a dissolution rate less than that of the reference preparation and are not similar to the reference preparation.

[0094] For those skilled in the art, it is obvious that the present invention is not limited to the details of the above - mentioned exemplary embodiments, and without departing from the spirit or basic characteristics of the present invention, the present invention can be implemented in other specific forms. Therefore, from any point of view, the embodiments should be regarded as exemplary and non - restrictive. The scope of the present invention is defined by the appended claims rather than the above description. Therefore, all changes falling within the meaning and scope of the equivalent elements of the claims are intended to be included in the present invention.

[0095] In addition, it should be understood that although this specification is described according to embodiments, not every embodiment only contains an independent technical solution. This narrative way of the specification is only for clarity. Those skilled in the art should regard the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A lamotrigine tablet, characterized in that: The invention comprises the following raw materials in parts by weight: 45-55 parts of lamotrigine, 45-55 parts of lactose, 45-55 parts of microcrystalline cellulose, 4.5-5.5 parts of sodium starch glycolate, 4.5-5.5 parts of povidone K30, 0.36-0.44 parts of yellow iron oxide and 0.72-0.88 parts of magnesium stearate.

2. The lamotrigine tablet according to claim 1, characterized in that The weight ratio of lamotrigine, lactose and microcrystalline cellulose is 1:(0.96-1.04):(0.96-1.04).

3. The lamotrigine tablet according to claim 1, characterized in that: The weight ratio of lamotrigine, sodium starch glycolate and povidone K30 is 10:(0.96-1.04):(0.96-1.04).

4. The lamotrigine tablet according to claim 1, characterized in that: The lamotrigine particle size D90 is 25 μm±5 μm.

5. The method for preparing the lamotrigine tablet according to any one of claims 1 to 4, characterized in that: The steps include: Prepare raw materials: lamotrigine, lactose, microcrystalline cellulose, sodium starch glycolate, povidone K30, yellow iron oxide and magnesium stearate; Mixing lamotrigine, lactose, yellow ferric oxide and microcrystalline cellulose to prepare a mixed powder; Mixing povidone K30 and water to prepare an adhesive; The mixed powder is mixed with a portion of sodium carboxymethyl starch, and then a binder is added to form a soft material; The soft material is wet granulated, dried, and dry granulated to obtain dry granules; The dry granules, magnesium stearate and the remaining sodium starch glycolate are mixed and tableted.

6. The method for preparing lamotrigine tablets according to claim 5, characterized in that: When the mixed powder is mixed with part of sodium carboxymethyl starch, the mass of the sodium carboxymethyl starch used is 45%-50% of the total mass of the raw sodium carboxymethyl starch.

7. The method for preparing lamotrigine tablets according to claim 5, characterized in that: When the mixed powder and part of sodium starch glycolate are mixed, the stirring frequency is 18-22 Hz, the chopping frequency is 25-30 Hz, and the time is 20-30 min.

8. The method for preparing lamotrigine tablets according to claim 5, characterized in that: The drying operation is to dry at 60° C.-70° C. until the moisture content is 1%-3.5%.

9. The method for preparing lamotrigine tablets according to claim 5, characterized in that: When the dry particles, magnesium stearate and the remaining sodium starch glycolate are mixed, the rotation speed is 10 r / min-20 r / min and the time is 8-15 min.

10. The method for preparing lamotrigine tablets according to claim 5, characterized in that: The wet granulation is performed by using a 18-24 mesh sieve, and / or the dry granulation is performed by using a 20-26 mesh sieve.

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