Lamotrigine composition and preparation process thereof

Abstract

The invention discloses a lamotrigine composition and a preparation process thereof. The lamotrigine composition is prepared from the following raw materials in mass concentration: 20-40% of lamotrigine, 30-40% of lactose monohydrate, 30-40% of microcrystalline cellulose, 1-4% of a disintegrating agent and 0.3-1% of magnesium stearate, and the total amount is 100%. The disintegrating agent is polyvinylpolypyrrolidone or sodium carboxymethyl starch. According to the lamotrigine composition provided by the invention, novel direct-mixing type auxiliary materials are adopted, the formula composition is simplified under the condition that the same in-vitro release target as a reference preparation is achieved, and the qualification of a product is further improved. According to the invention, a direct-mixing tabletting process is adopted, so that the production process is greatly simplified, and the production cost is reduced; water vapor and high temperature are avoided in the production process, and the stability of the product is ensured; the lamotrigine tablet prepared by the process has the advantages of uniform weight, complete appearance, no sticking and top cracking and the like, and is suitable for industrial production.

Description

(1) Technical Field

[0001] The present invention belongs to the field of medicine, and particularly relates to a lamotrigine composition and its preparation process. (2) Background Art

[0002] Lamotrigine tablets are a sodium channel regulator that can reduce the conduction of the nervous system and are widely used clinically for the treatment of epilepsy, being a first-line drug for epilepsy. Currently, information on the listing of similar products has been retrieved in countries such as the United States and the United Kingdom, and it was approved for listing in China in July 1996.

[0003] Lamotrigine is a compound sensitive to humidity and heat and will degrade under humid and hot conditions. Under accelerated conditions (40°C / 75% relative humidity) for 24 hours, the related substances (impurity C) increase significantly.

[0004]

[0005] The original manufacturer, The Wellcome Foundation Limited (UK), disclosed a drug combination containing lamotrigine in a world patent (application number PCT / GB1995 / 002865, publication number WO / 1996 / 017611, publication date June 1, 1996) using povidone K30 solution as a binder, lactose, microcrystalline cellulose or starch as a filler, and obtaining particles with the target particle size distribution by fluidized bed spray granulation. Although this method can prepare the required particles, the production process is complex, the equipment requirements are high, and a large amount of humidity and heat are introduced during the preparation process, posing a potential risk to the growth of impurities. Using this complex process may be limited by the level of excipients at that time.

[0006] A Chinese patent (application number 202311559251.9, publication number CN117442576A, publication date January 26, 2024) disclosed a lamotrigine preparation composition and its preparation method, using povidone K30 as a binder, for premixing, granulation, drying, sizing, total mixing, tabletting and packaging (the process flow is referred to Figure 2 ). Because a large amount of water and high temperature are introduced during the production process, it is easy to cause the increase of related substances. In addition, this process is complex, consumes a large amount of labor and energy, and is not a green and economical process route.

[0007] Most of the lamotrigine tablets on the market currently adopt the wet granulation process. Specifically, an aqueous solution of polyvinylpyrrolidone K30 is used for wet granulation of lamotrigine, followed by premixing, granulation, drying, sieving, blending, tabletting, and packaging to obtain lamotrigine tablets. However, a large amount of moisture and heat are introduced during the production process, which may potentially affect product impurities. At the same time, the traditional wet granulation process requires a large amount of labor and consumes a large amount of energy, and it is not a green and economical process route.

[0008] The package insert of the reference preparation produced by The Wellcome Foundation Limited shows that the product is completely absorbed in the intestine after oral administration and has no obvious first-pass metabolism. The highest concentration is reached in 2.5 hours. The dissolution rate of this reference preparation in different biorelevant media is very fast. To meet the requirements of bioequivalence, the disintegration and dissolution rates of the generic drug should also be very fast and consistent with the trend of the reference preparation.

[0009] Therefore, it is necessary to develop a lamotrigine composition and its preparation process that are simple to produce and conducive to maintaining product stability. (III) Summary of the Invention

[0010] The object of the present invention is to provide a lamotrigine composition and its preparation process. The lamotrigine composition of the present invention uses high-quality performance excipients and combines a simple, stable, and efficient direct compression tabletting process. The prepared tablets show a release trend consistent with that of the reference preparation and perform well in the stability comparative study, with better disintegration performance and related substance levels, solving the problems of complex process, high energy consumption, and easy generation of impurities in the existing methods.

[0011] The technical solution adopted by the present invention is as follows:

[0012] The present invention provides a lamotrigine composition, which is composed of the following raw materials in mass concentration: lamotrigine 20 - 40%, lactose monohydrate 30 - 40%, microcrystalline cellulose 30 - 40%, disintegrant 1 - 4%, magnesium stearate 0.3 - 1%, with a total of 100%; the disintegrant is crospovidone or sodium carboxymethyl starch.

[0013] Further, preferably, the lamotrigine composition is composed of the following raw materials in mass concentration: lamotrigine 31.25%, lactose monohydrate 32.625%, microcrystalline cellulose 32.625%, crospovidone or sodium carboxymethyl starch 3%, magnesium stearate 0.5%.

[0014] Further, the models of the lactose monohydrate include FlowLac90 or Super Tab 14SD.

[0015] Further, the cross-linked povidone model includes cross-linked povidone XL or cross-linked povidone XL-10, the sodium carboxymethyl starch model is Type A, and the cross-linked povidone and sodium carboxymethyl starch can achieve the same disintegration effect, and sodium carboxymethyl starch is more preferred.

[0016] The present invention also provides a preparation process of the lamotrigine composition, and the preparation process includes the following steps:

[0017] (1) First mixing: According to the formula amount, add lamotrigine, lactose monohydrate, microcrystalline cellulose and disintegrant into a mixer, and mix for 5 - 10 min;

[0018] (2) Second mixing: Add the formula amount of magnesium stearate into the mixer in step (1), and continue to mix for 5 - 10 min;

[0019] (3) Tabletting: Tablettize the total mixed granules in step (2), and keep the hardness at 40 - 80 N;

[0020] (4) Packaging: Perform aluminum-plastic blister packaging on the coated tablets obtained in step (3).

[0021] Further, the mixing parameters in steps (1) and (2) can adopt conventional parameters, and control the mixing speed at 10 - 25 rpm.

[0022] Further, for the aluminum-plastic packaging in step (4), select Aclar high-barrier transparent hard sheet (polyvinyl chloride / polyoxyethylene solid medicinal composite hard sheet) as the material.

[0023] The lamotrigine tablets prepared by the method of the present invention can be used for the treatment of epilepsy.

[0024] Compared with the prior art, the beneficial effects of the present invention are mainly reflected in:

[0025] (1) The lamotrigine composition provided by the present invention adopts a new type of direct mixing model excipient. Under the condition of achieving the same in vitro release target as the reference preparation (The Wellcome Foundation Limited), the formula composition is simplified, and the product quality is further improved.

[0026] (2) The present invention adopts a direct mixing tabletting process, which greatly simplifies the production process and reduces the production cost; water vapor and high temperature are avoided during the production process to ensure the stability of the product; the disintegration time limit and dissolution degree of the prepared tablets are consistent with those of the reference preparation; excellent water vapor isolation packaging is adopted to ensure the stability of the product during storage to the greatest extent; the lamotrigine tablets prepared according to the process of the present invention have the advantages of uniform tablet weight, complete appearance, no sticking, punching and cracking, etc., and are suitable for industrial production. (IV) Description of the Drawings

[0027] Figure 1 This is the process flow chart for the preparation of the present invention.

[0028] Figure 2 This is the process flow chart of the existing preparation process.

[0029] Figure 3 This is the dissolution curve of the lamotrigine tablets prepared in Example 1 and the reference preparation in 0.1N HCl medium (paddle method, 900 mL, 50 rpm).

[0030] Figure 4 This is the dissolution curve of the lamotrigine tablets prepared in Example 1 and the reference preparation in pH 4.5 acetate buffer medium (paddle method, 900 mL, 50 rpm).

[0031] Figure 5 This is the dissolution curve of the lamotrigine tablets prepared in Example 1 and the reference preparation in pH 6.8 phosphate buffer medium (paddle method, 900 mL, 50 rpm). (V) Specific Embodiments

[0032] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto: In the embodiments of the present invention, lamotrigine is sourced from Huahai Pharmaceutical, with the batch number 21120801. The mixer is an HSD-50 hopper mixer. The aluminum-plastic packaging selects (Aclar) high-barrier transparent hard sheet as the material.

[0033] Example 1, Direct Compression Tablet Process

[0034] 1. Formula

[0035] Table 1, Mass Concentration Formula of Lamotrigine Composition

[0036] Component Use Dosage (for 1000 tablets) Lamotrigine Active ingredient 31.25％ Lactose monohydrate (Super Tab 14SD) Filler 32.625％ Microcrystalline cellulose (PH112) Filler 32.625％ Sodium carboxymethyl starch (type A) Disintegrant 3％ Magnesium stearate Lubricant 0.5％

[0037] 2. Preparation Process:

[0038] (1) First Mixing: According to the formula amount, add lamotrigine, lactose monohydrate, microcrystalline cellulose, and sodium carboxymethyl starch to the mixer, and mix at 12 rpm for 10 min;

[0039] (2) Second Mixing: Add the formula amount of magnesium stearate to the mixer in step (1), and continue to mix at 12 rpm for 5 min;

[0040] (3) Tableting: Table the total mixed granules in step (2), and keep the hardness at 40 - 80 N to obtain coated tablets. Each tablet contains 50 mg of lamotrigine, with uniform tablet weight, complete appearance, and no sticking, punching, or cracking;

[0041] (4) Packaging: The coated tablets obtained in step (3) are subjected to aluminum-plastic blister packaging to isolate water vapor and ensure the stability of the product during storage to the greatest extent possible.

[0042] 3. Performance Testing

[0043] The evaluation contents include fluidity, disintegration time limit, dissolution rate, and accelerated stability.

[0044] (1) Fluidity

[0045] The quality of fluidity is reflected by the angle of repose: the smaller the angle of repose, the smaller the frictional force and the better the fluidity. The angle of repose is measured using an intelligent powder tester, and the results are shown in Table 5.

[0046] (2) Disintegration Time Limit:

[0047] Six test samples are taken and should completely disintegrate within 10 minutes. The results are shown in Table 5.

[0048] (3) Dissolution Rate:

[0049] Detection is carried out according to the dissolution rate determination method (Second Method for the Determination of Dissolution and Release, Part IV of the Chinese Pharmacopoeia 2020 Edition, 0931). The results are shown in Table 6.

[0050] (4) Accelerated Stability Investigation:

[0051] Detection is carried out according to the guiding principles for stability tests (Guiding Principles for the Stability Tests of Raw Drugs and Preparations, Part IV of the Chinese Pharmacopoeia 2020 Edition, 9001). The dissolution curves of lamotrigine tablets and the reference preparation in 0.1N HCl medium (paddle method, 900 mL, 50 rpm), pH 4.5 acetate buffer medium (paddle method, 900 mL, 50 rpm), and pH 6.8 phosphate buffer medium (paddle method, 900 mL, 50 rpm) are shown in Figure 3 、 4 、5. The medium preparation and dissolution method are both referred to the "Guiding Principles for the Technology of Dissolution Tests for Oral Solid Dosage Forms".

[0052] Example 2, Direct Compression Tablet Process

[0053] 1. Formula (the lactose model is changed to Flow90 compared to Example 1)

[0054] Table 2, Mass Concentration Formula of Lamotrigine Composition

[0055] Component Use Dosage (for 1000 tablets) Lamotrigine Active ingredient 31.25％ Lactose monohydrate (FlowLac90) Filler 32.625％ Microcrystalline cellulose (PH112) Filler 32.625％ Sodium carboxymethyl starch (type A) Disintegrant 3％ Magnesium stearate Lubricant 0.5％

[0056] 2. Preparation Method:

[0057] (1) Mixing 1: According to the formulation amounts, add lamotrigine, lactose monohydrate, microcrystalline cellulose, and sodium carboxymethyl starch to a mixer, and mix at 12 rpm for 10 min;

[0058] (2) Mixing 2: Add the formulation amount of magnesium stearate to the mixer in step (1), and continue mixing at 12 rpm for 5 min;

[0059] (3) Tableting: Tablet the total mixed granules in step (2), keep the hardness at 40 - 80 N to obtain coated tablets, with each tablet containing 50 mg of lamotrigine, uniform tablet weight, complete appearance, and no sticking, punching, or cracking;

[0060] (4) Packaging: Perform aluminum-plastic blister packaging on the coated tablets obtained in step (3).

[0061] 3. Performance testing

[0062] Use the method of Example 1 to test the flowability and disintegration time limit of the lamotrigine tablets, and the results are shown in Table 5.

[0063] Example 3, direct mixing and tableting process

[0064] 1. Formulation (the disintegrant is changed to crospovidone (XL) compared to Example 1)

[0065] Table 3. Quality concentration formulation of the lamotrigine composition

[0066] Component Use Dosage (for 1000 tablets) Lamotrigine Active ingredient 31.25％ Lactose monohydrate (Super Tab 14SD) Filler 32.625％ Microcrystalline cellulose (PH112) Filler 32.625％ Crospovidone (XL) Disintegrant 3％ Magnesium stearate Lubricant 0.5％

[0067] 2. Preparation method:

[0068] (1) Mixing 1: According to the formulation amounts, add lamotrigine, lactose monohydrate, microcrystalline cellulose, and crospovidone to a mixer, and mix for 10 min;

[0069] (2) Mixing 2: Add the formulation amount of magnesium stearate to the mixer in step (1), and continue mixing for 5 min;

[0070] (3) Tableting: Tablet the total mixed granules in step (2), keep the hardness at 40 - 80 N to obtain coated tablets, with each tablet containing 50 mg of lamotrigine, uniform tablet weight, complete appearance, and no sticking, punching, or cracking;

[0071] (4) Packaging: Perform aluminum-plastic blister packaging on the coated tablets obtained in step (3).

[0072] 3. Performance testing

[0073] Use the method of Example 2 to test the flowability and disintegration time limit of the lamotrigine tablets, and the results are shown in Table 5.

[0074] Comparative Example 1, wet granulation process

[0075] 1. Formulation

[0076] Table 4. Quality concentration formulation of lamotrigine composition

[0077] Component Use Dosage (for 1000 tablets) Lamotrigine Active ingredient 31.25 Lactose monohydrate (Super Tab 14SD) Filler 30.875 Microcrystalline cellulose (PH112) Filler 30.875 Povidone K30 Binder 2.0 Sodium carboxymethyl starch Disintegrant 3.0 Magnesium stearate Lubricant 1.5 Yellow iron oxide Pigment 0.5

[0078] 2. Preparation method:

[0079] 1) Preparation of binder: Weigh polyvinylpyrrolidone K30 according to the formulation amount, and add purified water to prepare a 5% solution by mass concentration;

[0080] 2) Granulation: According to the formulation amount, add lamotrigine, lactose monohydrate, microcrystalline cellulose, sodium carboxymethyl starch and yellow iron oxide into a wet granulator and mix for 10 minutes. Then slowly add the binder and stir for 3 minutes to make a soft material that can be formed into a ball by hand and dispersed when lightly pressed. Then, use a swing granulator for wet screening, and control the mesh number of the sieve to be 24 meshes;

[0081] 3) Drying: Put the wet granules into a fluidized bed dryer for drying, at a temperature of 50 °C for about 30 minutes, and control the moisture content to be less than 3.0% to obtain dry granules;

[0082] 4) Screening: Screen the dry granules in a swing granulator, and control the mesh number of the sieve to be 24 meshes;

[0083] 5) Total mixing and tableting: Add magnesium stearate and dry granules in accordance with the formulation amount to a V-type mixer, control the mixing speed at 15 rpm and the mixing time at 5 minutes, and directly tablet, controlling the hardness to be between 40 - 80 N;

[0084] 6) Packaging: Perform aluminum-plastic blister packaging on the coated tablets obtained in step 5).

[0085] 3. Performance testing

[0086] Adopt the method of Example 2 to test the fluidity, disintegration time limit, dissolution rate and accelerated stability of lamotrigine tablets, and the results are shown in Table 5 and Table 6.

[0087] Table 5. Fluidity and disintegration time of lamotrigine tablets in Examples 1 - 3 and Comparative Example 1

[0088] Sample Flowability Disintegration time Example 1 38.2° 30 seconds Example 2 43.1° 50 seconds Example 3 38.7° 1 minute 20 seconds Comparative Example 1 45.6° 2 minutes 05 seconds Reference preparation NA 45 seconds

[0089] In Table 5, the reference preparation is a commercially available product, with the batch number 849N and the manufacturer The Wellcome Foundation Limited. NA indicates not applicable.

[0090] The results in Table 5 show that the lamotrigine tablets prepared by the methods of Examples 1 and 3 both have good fluidity, both below 40 °, the fluidity of Example 2 exceeds 40 °, and Super Tab 14SD is used as the preferred model.

[0091] In Example 3, the disintegration time was significantly longer than that in Example 1, indicating that sodium carboxymethyl starch can exert a better disintegration effect compared with crospovidone. Sodium carboxymethyl starch is used as the preferred disintegrant.

[0092] In summary, Example 1 exhibited the optimal fluidity and disintegration performance, and further studies on its stability and in vitro release were carried out.

[0093] In Comparative Example 1, the fluidity was poor and the disintegration time limit was long.

[0094] Table 6. Comparison results of the accelerated tests of Example 1, Comparative Example 1 and the reference preparation

[0095]

[0096] The results in Table 6 show that the lamotrigine tablets prepared by the method of Example 1 performed better than those of Comparative Example 1 and the reference preparation, and had good stability.

[0097] Figure 3 、 4 、5 indicate that the dissolution curves of the lamotrigine tablets prepared in Example 1 in different media were consistent with those of the reference preparation.

[0098] Based on the ideal embodiments of the present invention as an inspiration, through the above description, relevant personnel can make various changes and modifications completely within the scope of not deviating from the technical idea of this invention. The technical scope of this invention is not limited to the content in the specification, and its technical scope must be determined according to the scope of the claims.

Claims

1. A lamotrigine composition, characterized in that: The lamotrigine composition is composed of raw materials with the following mass concentrations: 20-40% lamotrigine, 30-40% lactose monohydrate, 30-40% microcrystalline cellulose, 1-4% disintegrant, 0.3-1% magnesium stearate, with a total amount of 100%; the disintegrant is cross-linked polyvinylpyrrolidone or sodium carboxymethyl starch.

2. The lamotrigine composition according to claim 1, characterized in that: The lamotrigine composition is composed of raw materials with the following mass concentrations: 31.25% lamotrigine, 32.625% lactose monohydrate, 32.625% microcrystalline cellulose, 3% disintegrant, and 0.5% magnesium stearate.

3. The lamotrigine composition according to claim 1, characterized in that: The lactose monohydrate types include FlowLac90 or Super Tab 14SD.

4. The lamotrigine composition according to claim 1, characterized in that: The cross-linked polyvinylpyrrolidone includes cross-linked polyvinylpyrrolidone XL or cross-linked polyvinylpyrrolidone XL-10, and the model of sodium carboxymethyl starch is Type A.

5. A process for preparing the lamotrigine composition according to claim 1, characterized in that: The preparation process comprises the following steps: (1) Mixing 1: Add lamotrigine, lactose monohydrate, microcrystalline cellulose and disintegrant into a mixer according to the formula amount and mix for 5 to 10 minutes; (2) Mixing 2: Add the formulated amount of magnesium stearate into the mixer of step (1) and continue mixing for 5 to 10 minutes; (3) tableting: tableting the mixed granules in step (2) with a hardness of 40 to 80 N; (4) Packaging: The coated tablets obtained in step (3) are packaged in aluminum-plastic blisters.

6. The preparation process according to claim 5, characterized in that: The mixing speed of steps (1) and (2) is 10-25 rpm.

7. The preparation process according to claim 5, characterized in that: The material of the aluminum-plastic in step (4) is Akra high-barrier transparent hard sheet.

Images