A lamotrigine formulation composition and a method of preparing the same

Abstract

The application belongs to the technical field of pharmaceutical preparation, and particularly relates to a lamotrigine preparation composition and a preparation method thereof, which comprises the following components by weight: lamotrigine 50 parts, lactose 47 parts, microcrystalline cellulose 50-60 parts, sodium carboxymethyl starch 4 parts, povidone K30 2.5 parts, magnesium stearate 1 part, and yellow iron oxide 0.1 part; the particle size D90 of the lamotrigine is 47 mu m+ / -5 mu m, the particle size D90 of the lactose is 95 mu m+ / -10 mu m, and the particle size D90 of the microcrystalline cellulose is 49 mu m+ / -20 mu m; the application effectively reduces the impurity content of the lamotrigine preparation composition after long-term storage, and improves the stability of the drug.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a lamotrigine formulation composition and its preparation method. Background Technology

[0002] Lamotrigine is a voltage- and function-dependent blocker of voltage-gated sodium channels. Originally developed by GlaxoSmithKline, it was launched in Ireland in 1990. As a first-line antiepileptic drug, it can be used alone or in combination for the treatment of epilepsy and bipolar disorder, showing significant efficacy. It is safe for pregnant women and has a good safety profile. Clinical studies show that lamotrigine has the highest treatment retention index among new-generation antiepileptic drugs. A 2021 multicenter RCT study published in *The Lancet* showed that lamotrigine is a first-line treatment for patients with focal epilepsy and should become a standard treatment in future trials. This study does not support levetiracetam or zonisamide as first-line treatment for patients with focal epilepsy. In other countries, lamotrigine is also used to treat bipolar disorder and is safe for pregnant women, offering irreplaceable clinical advantages.

[0003] The main adverse reaction of lamotrigine tablets is skin adverse reaction. The drug instructions mention that the incidence of skin rash when taking lamotrigine is as high as 10%, and 2% of patients have to stop lamotrigine treatment due to skin rash. Because lamotrigine may cause severe hypersensitivity reactions with high mortality (such as toxic epidermal necrolysis, TEN, with a mortality rate of up to 50%), even if the drug is stopped in time, the condition may still worsen or even lead to death. To a certain extent, this has created a panic among clinicians about the use of lamotrigine, which has prevented lamotrigine from being used rationally in clinical practice.

[0004] Based on considerations of lamotrigine drug safety and risk prevention, improving the formulation and preparation process of lamotrigine tablets from the source of drug manufacturing can enhance the quality level of lamotrigine tablets and reduce the generation of related impurities during storage, which can reduce or avoid certain adverse reactions to some extent. Process impurities may be introduced during the synthesis of lamotrigine raw materials, such as 2,3-dichlorobenzoyl chloride, 2,3-dichlorobenzoyl cyanide, and 2,3-dichlorobenzoic acid (lamotrigine impurity I, referred to as impurity B in this text). During the storage of lamotrigine formulations, some degradation impurities may be generated, such as 2,3-dichlorobenzoic acid (impurity B), 3-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-5-(4H)-one (impurity C), and 6-(2,3-dichlorophenyl)-1,2,4-triazin-3,5-(2H,4H)-dione (impurity E). Chinese invention patent CN113156009A has developed a detection method that can effectively detect both process impurities and degradation impurities related to lamotrigine, providing a more sensitive and convenient detection method for in-depth research on the quality control of lamotrigine formulations.

[0005] The stability of a drug not only affects its efficacy but also leads to unpredictable safety risks. Lamotrigine tablets may develop various impurities during long-term storage, particularly impurity C, which increases rapidly. This affects the efficacy and safety of lamotrigine tablets. Existing methods for preparing lamotrigine tablets and the resulting tablets themselves still generate some impurities during storage, especially impurity C, which increases rapidly. Therefore, the stability of lamotrigine tablets needs further improvement. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a lamotrigine formulation composition and its preparation method, which effectively reduces the impurity content of the lamotrigine formulation composition after long-term storage, especially reduces the growth rate of impurity C and improves the stability of the drug.

[0007] The present invention relates to a lamotrigine formulation composition comprising the following raw and auxiliary materials in the indicated weight percentages: 50 parts lamotrigine, 47 parts lactose, 50-60 parts microcrystalline cellulose, 4 parts sodium carboxymethyl starch, 2.5 parts povidone K30, 1 part magnesium stearate, and 0.1 parts yellow iron oxide.

[0008] The lamotrigine:lactose:microcrystalline cellulose ratio is 50:47:(50-60)(w / w), the particle size D90 of the lamotrigine is 47μm±5μm, the particle size D90 of the lactose is 95μm±10μm, and the particle size D90 of the microcrystalline cellulose is 49μm±20μm.

[0009] The preparation method of the lamotrigine formulation composition is as follows: premixing the colorant mixture and the active ingredient mixture, granulating, drying, sizing, total mixing, and tableting to obtain the lamotrigine formulation composition; the colorant mixture is a mixture of partial lactose and yellow iron oxide; the active ingredient mixture is a mixture of lamotrigine, the remaining lactose, microcrystalline cellulose, and sodium carboxymethyl starch; during the granulation operation, a povidone K30 aqueous solution and water are added sequentially as binders; after drying and sizing the obtained wet granules, magnesium stearate of the prescribed amount is added for total mixing, and the mixed material is tableted to obtain the lamotrigine formulation composition.

[0010] Preferably, the lamotrigine:lactose:microcrystalline cellulose ratio is 50:47:55 (w / w), the particle size D90 of the lamotrigine is 45 μm, 47 μm, 48 μm, or 50 μm, the particle size D90 of the lactose is 95 μm or 98 μm, and the particle size D90 of the microcrystalline cellulose is 49 μm or 50 μm.

[0011] In the colorant mixture, the weight ratio of lactose to yellow iron oxide is 100:1 (w / w).

[0012] During the granulation process, a povidone K30 aqueous solution and water are added sequentially within 60 seconds as a binder.

[0013] The weight concentration of the polyvinylpyrrolidone K30 aqueous solution is 5%, and the weight ratio of the polyvinylpyrrolidone K30 aqueous solution to water is 10:0.5 to 2 (w / w).

[0014] The colorant mixture is passed through a 60-mesh sieve, the stirring speed of the granulation is 170 rpm ± 5%, the shearing speed is 1500 rpm ± 5%, and the wet granules after granulation are passed through a 16-mesh sieve.

[0015] The wet granules after granulation are dried at a temperature of 60-70°C, and the material is collected when the moisture content of the granules is controlled at 1.0%-4.0%.

[0016] The mixing process involves adding the prescribed amount of magnesium stearate for mixing, with a mixing speed of 10 r / min and a mixing time of 5 minutes.

[0017] The tablet weight of the lamotrigine formulation composition is 0.16g / tablet, and the hardness of the lamotrigine formulation composition tablet is 2kg to 5kg (according to the unit conversion of the hardness tester, 1kg = 9.8N, the same below).

[0018] A method for preparing a lamotrigine formulation composition is as follows:

[0019] 1. Preparation: Weigh out the prescribed amounts of lamotrigine, microcrystalline cellulose, sodium carboxymethyl starch, lactose, and yellow iron oxide.

[0020] 2. Sieving: After preparing the materials, weigh 2 kg of lactose and sieve it together with all the yellow iron oxide (or the materials sieved together in the previous sieve) in 3 batches through a 60-mesh sieve.

[0021] 3. Granulation: (1) Preparation of binder: ① 5% povidone K30 solution: Weigh 500g of the prescribed amount of povidone K30, add water to a total weight of 10.0kg, stir to dissolve and set aside (the solution should be clear and transparent). ② Purified water: Weigh 1.05kg of purified water and set aside. (2) Making wet pellets: The mixture of lactose and yellow iron oxide after co-sieving is added to the 250B high-efficiency wet pellet mill along with other materials. The low-speed stirring (170 rpm) and low-speed shearing (1500 rpm) of the 250B high-efficiency wet pellet mill are turned on simultaneously. After premixing for 5 minutes, the machine is stopped and the inner wall, top and paddle of the pot are cleaned. After sealing the pot lid, the low-speed stirring and low-speed shearing are turned on simultaneously. All of the 5% povidone K30 solution and purified water as binder are added in sequence (within 60 seconds). After stirring and shearing for 90 seconds, the machine is stopped. The inner wall, top and paddle of the pot are cleaned. After sealing the pot lid, the low-speed stirring and low-speed shearing are turned on again for 30 seconds. The soft material is then discharged. The soft material is made into wet pellets by passing it through a 16-mesh nylon sieve using a gyratory pellet mill.

[0022] 4. Drying: Spread the wet granules evenly in a stainless steel tray, with a thickness not exceeding 2cm, and place it in a hot air circulating oven at 65℃ to dry until the moisture content of the granules is controlled at 2%.

[0023] 5. Granulation: The dried granules are granulated by passing them through an 18-mesh nylon sieve using a vibrating pellet mill.

[0024] 6. Blending: Place the granulated particles into an HF cone mixer, add the prescribed amount of magnesium stearate, set the speed to 10 rpm, blend for 5 minutes, and then discharge.

[0025] 7. Tableting: Calculate the tablet weight based on the particle content. Use a ZP-35B rotary tablet press with an 8.5mm shallow die to test and adjust the tablet weight (theoretical tablet weight is 0.16g / tablet). After the friability, hardness, and appearance are qualified, begin formal tableting. The hardness of the unprocessed tablets should be controlled between 2 and 5kg.

[0026] The beneficial effects of the present invention are that the lamotrigine formulation prepared by the present invention has good process compliance. Furthermore, after optimizing the ratio and particle size of lamotrigine, lactose, and microcrystalline cellulose, the lamotrigine formulation prepared by the present invention shows a slower growth trend of impurity C and a slower dissolution trend in the stability test. Attached Figure Description

[0027] Figure 1 This is a flowchart of the preparation process of the present invention.

[0028] Figure 2 The dissolution curves of three batches of the reference formulation and process validation were compared in June (0.1 mol / L hydrochloric acid solution).

[0029] Figure 3 Dissolution profiles of three batches (pH 4.0 acetate buffer) were compared at 6 months for reference formulation and process validation.

[0030] Figure 4 Dissolution profiles of three batches (pH 5.5 phosphate buffer) at 6 months prior to reference formulation and process validation are shown in the comparison chart.

[0031] Figure 5 Dissolution profiles of three batches for reference formulation and process validation at month 0 (pH 6.8 phosphate buffer).

[0032] Figure 6 Dissolution profiles of three batches over a long period of 6 months (pH 6.8 phosphate buffer) were used as a reference formulation and for process validation.

[0033] Figure 7 This is a comparison chart of the dissolution profiles of three batches (pH 6.8 phosphate buffer) at the midpoint of June for the reference formulation and process validation.

[0034] Figure 8 The dissolution profiles of three batches (pH 6.8 phosphate buffer) were compared over 6 months for the reference formulation and process validation. Detailed Implementation

[0035] The research group previously developed a method for detecting lamotrigine-related substances (Chinese Invention Patent CN113156009A), which can effectively detect the aforementioned process impurities and degradation impurities related to lamotrigine simultaneously. This method was used to conduct quality control research on lamotrigine formulation compositions. Previous formulation studies by the group revealed that to achieve dissolution behavior similar to the original lamotrigine tablets (Libiton), the particle size and dosage of lamotrigine, lactose, and microcrystalline cellulose are significantly related. Initially, the particle size range (D90) of lamotrigine was set at 36–62 μm. During the research process, the group unexpectedly discovered that the ratio of lamotrigine, lactose, and microcrystalline cellulose, as well as the particle sizes of lamotrigine, lactose, and microcrystalline cellulose, can significantly affect the quality stability of the developed lamotrigine formulation composition, specifically the growth rate of impurity C, impurity B, and unknown impurities. Impurity C is an impurity resulting from the oxidative degradation of lamotrigine. The growth trend of impurity C in the lamotrigine formulation prepared in this invention is slower, which may be largely related to the co-sieving of lactose and yellow iron oxide, as well as the proportions and particle sizes of lamotrigine, lactose, and microcrystalline cellulose. Specific formulation ratios and particle sizes for the lamotrigine formulation are shown in "Example 1".

[0036] Experiment 1: Particle size analysis of raw materials and excipients for lamotrigine tablets

[0037] Example 1

[0038] The weight composition of each raw material and excipient of a lamotrigine tablet (50mg / tablet, batch size 1000 tablets) is shown in Table 1.

[0039] The particle size D90 of the lamotrigine is 47 μm, that of the lactose is 95 μm, and that of the microcrystalline cellulose is 49 μm.

[0040] The particle size determination involved in this invention is performed according to the third method (light scattering method) of the General Chapter 0982 of the Chinese Pharmacopoeia, Part IV (the same applies below).

[0041] Table 1. Formulation composition of 50mg unit dose products (based on 1000 tablets)

[0042]

[0043] The preparation method is as follows: (This preparation method is a small-scale process using laboratory equipment)

[0044] ① Premix: Weigh half of the lactose and yellow iron oxide according to the prescription, disperse them through a 60-mesh sieve, and then place them in a G6 wet mixing granulator with the prescription amount of lamotrigine, the remaining lactose, microcrystalline cellulose and sodium carboxymethyl starch. Stir (4r / s) and cutter (25r / s) simultaneously and mix for 3 minutes.

[0045] ② Granulation and drying:

[0046] Preparation of 5% Povidone K30 solution: Weigh the prescribed amount of povidone K30 and add water to prepare a 5% povidone K30 solution. Stir to dissolve the solution. The solution should be clear and transparent. Set aside for later use.

[0047] Purified water: Weigh out approximately 3.5% of the premixed material amount of purified water and set aside.

[0048] Add the prescribed amount of 5% povidone K30 solution and purified water to the premixed material in sequence to prepare a soft material. Stir (4r / s) and cutter (25r / s) are turned on simultaneously for 3 minutes. Discharge the material and granulate it using a 16-mesh sieve. Spread the wet granules evenly on a tray and dry them in a 70℃ oven.

[0049] ③ Granulation and mixing: Granulate the dried granules through an 18-mesh sieve. Based on the granule yield, add magnesium stearate according to the prescription ratio and mix for 5 minutes using a VH-5V mixer.

[0050] ④ Tableting: Tableting is performed using a DP30A single-punch tablet press with a Φ8.5mm round punch and a hardness of 5-7kg. The theoretical tablet weight is 160mg, and the weight difference is ≤±7%.

[0051] Comparative Examples 1-6

[0052] The differences between Comparative Examples 1-6 and Example 1 are shown in the table below. The other steps are the same as in Example 1.

[0053] Table 2. Material proportions and particle size distribution for Example 1 and Comparative Examples 1-6

[0054]

[0055] Accelerated stability tests were conducted on the above comparative examples. The samples were placed at a temperature of 40℃±2℃ and a relative humidity of 75%±5% for 3 months. The impurity content of the samples after these tests was shown in the table below.

[0056] Table 3. Stability study of lamotrigine tablets prepared in Example 1 and Comparative Examples 1-6

[0057]

[0058] Note: *The dissolution situation mentioned refers to the dissolution experiment in "4. Dissolution determination method" using 0.1 mol / L hydrochloric acid solution as the dissolution medium, with sampling and testing at 5, 10, 15 and 20 minutes respectively.

[0059] The data in the table above show that the amount of microcrystalline cellulose used, as well as the particle size variations of lamotrigine, lactose, and microcrystalline cellulose, all affect the quality stability of lamotrigine tablet formulations. However, the data from the accelerated 3-month stability test of the lamotrigine tablet formulations prepared in Example 1 and Comparative Examples 1-6 show that the detected values ​​of impurity B, impurity C, maximum single impurity, and total impurities are all within the limits of the current quality standards (see the standard limits in "2. Related Substances Detection Methods" below).

[0060] The data in the table above shows that the ratio of lamotrigine:lactose:microcrystalline cellulose is 50:47:(50-60), where the D90 of lamotrigine is 47μm±5μm, the D90 of lactose is 95μm±10μm, and the D90 of microcrystalline cellulose is 49μm±20μm. In the accelerated stability study of samples after 3 months, the detected values ​​of impurity B, impurity C, maximum single impurity, and total impurities of the prepared lamotrigine tablets were all within the limits specified by the quality standard, indicating good quality stability. The preferred formulation is Example 1: lamotrigine:lactose:microcrystalline cellulose = 50:47:55 (w / w), with a lamotrigine D90 of 47μm, a lactose D90 of 95μm, and a microcrystalline cellulose D90 of 49μm. This formulation exhibits the best quality stability. Of course, this invention is not limited to a specific D90 value. For example, the lamotrigine tablets prepared from different batches of lamotrigine raw material with D90 values ​​of 45μm, 48μm and 50μm respectively in the following examples can maintain the quality stability of the prepared lamotrigine tablets.

[0061] Based on dissolution data, the particle size of lactose and microcrystalline cellulose had little effect on the dissolution of lamotrigine tablets at 0 months, but it had a significant impact on the storage stability of the lamotrigine tablet formulation. In particular, changes in lactose particle size significantly affected the quality stability of lamotrigine tablets. Previous formulation studies have found that changes in the content of lactose and microcrystalline cellulose significantly affect dissolution. The data in the table above show that even slight changes in the content of microcrystalline cellulose also had a certain impact on the dissolution of lamotrigine tablet formulations at 0 months.

[0062] Appendix. The detection method involved in this invention is as follows:

[0063] 1. Identification of characteristics is done by visual observation;

[0064] 2. The detection methods for related substances shall refer to the methods described in CN113156009A;

[0065] The related substance limits for the shelf life of lamotrigine tablets are as follows: If there are impurity peaks in the chromatogram of the test solution, the peak area of ​​impurity B (relative retention time of approximately 0.8) calculated by multiplying the corrected peak area by a correction factor of 2.7 shall not exceed the area of ​​the main peak of the control solution (0.2%); the peak area of ​​impurity C (relative retention time of approximately 1.7) calculated by multiplying the corrected peak area by a correction factor of 1.4 shall not exceed 2.5 times (0.5%) the area of ​​the main peak of the control solution; the area of ​​any other single impurity peak shall not exceed the area of ​​the main peak of the control solution (0.2%); and the sum of the areas of all impurity peaks calculated by multiplying the corrected peak areas shall not exceed 3.75 times (0.75%) the area of ​​the main peak of the control solution.

[0066] 3. Content determination method: Determined by high performance liquid chromatography (General Rule 0512).

[0067] Chromatographic conditions and system suitability test: Octadecylsilane-bonded silica gel was used as the packing material; methanol-0.5% triethylamine solution (pH adjusted to 4.5 with phosphoric acid) (40:60) was used as the mobile phase; the detection wavelength was 265 nm; the theoretical plate number, calculated based on the lamotrigine peak, should not be less than 5000; and the resolution between the lamotrigine peak and adjacent impurity peaks should meet the requirements.

[0068] Assay: Accurately weigh 20 tablets of this product, grind them into a fine powder, accurately weigh an appropriate amount (approximately equivalent to 25 mg of lamotrigine), add the mobile phase to dissolve and dilute to prepare a solution containing approximately 25 μg of lamotrigine per ml, shake well, filter, and use the filtrate as the test solution. Accurately inject 20 μl of the test solution into the chromatograph and record the chromatogram. Separately, take an appropriate amount of lamotrigine reference standard, add the mobile phase to dissolve and dilute to prepare a solution containing approximately 25 μg of lamotrigine per ml, and use this as the reference solution. Determine the result using the same method. Calculate the result by peak area using the external standard method.

[0069] 4. Method for determining dissolution: Determined by high performance liquid chromatography (General Rule 0512).

[0070] Chromatographic conditions and system suitability test: same as content determination.

[0071] Assay: Take this product and perform the dissolution and release assay (General Rule 0931, Method II). Use 900 ml each of 0.1 mol / L hydrochloric acid solution, pH 4.0 acetate buffer, pH 5.5 phosphate buffer, and pH 6.8 phosphate buffer as dissolution media (the preparation of these four dissolution media is well known to those skilled in the art). The rotation speed is 50 rpm. Operate according to the method. At 5, 10, 15, and 20 minutes (during the stability period, the sampling time points of 30, 45, and 60 minutes may be appropriately increased according to the sample dissolution), take 5 ml of the dissolution solution at each time, and add an equal volume of the same dissolution medium. Filter, and take the filtrate as the test solution. Accurately measure 20 μl of the test solution and inject it into the liquid chromatograph, and record the chromatogram.

[0072] Take an appropriate amount of lamotrigine reference standard, dissolve it in an appropriate amount of methanol, and dilute it with the corresponding medium to prepare a solution containing approximately 25 μg of lamotrigine per 1 ml. Shake well and use this solution as the reference standard solution. Determine the solution using the same method.

[0073] The dissolution amount and cumulative dissolution amount of each tablet at each time point are calculated using the external standard method based on peak area.

[0074] 5. Dissolution test method: As described in 4, use 0.1 mol / L hydrochloric acid solution as the dissolution medium, take a sample for testing after 20 minutes, and the limit is 85% of the labeled amount, which should comply with the regulations.

[0075] Experiment 2: Process Investigation of Premixing and Wet Granulation Steps

[0076] This invention investigated the premixing and soft material preparation processes in Example 1 on production line equipment in a production workshop to examine the process feasibility and process compliance of transferring the laboratory-scale production process to the workshop production line equipment, as well as to study the quality control of lamotrigine tablets. The study found that the premixing process not only affects the compliance of the preparation process but also significantly impacts the quality stability of the prepared lamotrigine tablets. Specific investigations are as follows:

[0077] Example 2

[0078] The formulation ratio and particle size of raw materials and excipients in Example 2 are exactly the same as those in Example 1. Example 2 uses large-scale production equipment with a batch size of 200,000 tablets, and the dosage of each raw material and excipient is increased by 200 times, as shown in Table 4. Example 1 uses laboratory-scale equipment with a batch size of 1,000 tablets.

[0079] Table 4. Formulation composition of 50mg unit dose products (based on 200,000 tablets)

[0080]

[0081]

[0082] The preparation method of lamotrigine tablets, such as Figure 1 As shown, the batch number for lamotrigine tablets is 181105.

[0083] The preparation method of lamotrigine tablets includes the following steps:

[0084] 1. Preparation of materials: Weigh out the prescribed amounts of lamotrigine, microcrystalline cellulose, sodium carboxymethyl starch, lactose, and yellow iron oxide according to the production instructions.

[0085] 2. Sieving: After preparing the materials, weigh 2 kg of lactose and sieve it together with all the yellow iron oxide (or the materials sieved together in the previous sieve) in 3 batches through a 60-mesh sieve.

[0086] 3. Granulation: (1) Preparation of binder: ① 5% povidone K30 solution: Weigh 500g of the prescribed amount of povidone K30, add water to a total weight of 10.0kg, stir to dissolve and set aside (the solution should be clear and transparent). ② Purified water: Weigh 1.05kg of purified water and set aside. (2) Making wet pellets: The mixture of lactose and yellow iron oxide after co-sieving is added to the 250B high-efficiency wet pellet mill along with other materials. The low-speed stirring (170 rpm) and low-speed shearing (1500 rpm) of the 250B high-efficiency wet pellet mill are turned on simultaneously. After premixing for 5 minutes, the machine is stopped and the inner wall, top and paddle of the pot are cleaned. After sealing the pot lid, the low-speed stirring and low-speed shearing are turned on simultaneously. All of the 5% povidone K30 solution and purified water as binder are added in sequence (within 60 seconds). After stirring and shearing for 90 seconds, the machine is stopped. The inner wall, top and paddle of the pot are cleaned. After sealing the pot lid, the low-speed stirring and low-speed shearing are turned on again for 30 seconds. The soft material is then discharged. The soft material is made into wet pellets by passing it through a 16-mesh nylon sieve using a gyratory pellet mill.

[0087] 4. Drying: Spread the wet granules evenly in a stainless steel tray, with a thickness not exceeding 2cm, and place it in a hot air circulating oven at 65℃ to dry until the moisture content of the granules is controlled at 2%.

[0088] 5. Granulation: The dried granules are granulated by passing them through an 18-mesh nylon sieve using a vibrating pellet mill.

[0089] 6. Blending: Place the granulated particles into an HF cone mixer, add the prescribed amount of magnesium stearate, set the speed to 10 rpm, blend for 5 minutes, and then discharge.

[0090] 7. Tableting: Calculate the tablet weight based on the particle content. Use a ZP-35B rotary tablet press with an 8.5mm shallow die to test and adjust the tablet weight (theoretical tablet weight is 0.16g / tablet). After the friability, hardness, and appearance are qualified, begin formal tableting. The hardness of the unprocessed tablets should be controlled between 2 and 5kg.

[0091] 8. Inner and outer packaging and warehousing (routine operations in pharmaceutical factories, excluding technical details)

[0092] Comparative Example 7

[0093] Compared to Example 2, Comparative Example 7 differs in that lactose and yellow iron oxide are sieved separately during the sieving process. In the wet granulation process, lamotrigine, lactose, microcrystalline cellulose, sodium carboxymethyl starch, and yellow iron oxide are directly added to a 250B high-efficiency wet granulator. Simultaneously, the 250B high-efficiency wet granulator is started with low-speed stirring (170 rpm) and low-speed shearing (1500 rpm). After premixing for 5 minutes, the machine is stopped, and the inner wall, top, and material on the paddle are cleaned. Other steps are the same as in Example 2.

[0094] Comparative Example 8

[0095] Compared to Example 2, Comparative Example 8 differs in that, during the wet granulation process, after sealing the pot lid, low-speed stirring and low-speed shearing are simultaneously activated, and the entire mixture of 5% povidone K30 solution and purified water is quickly added as a binder (within 60 seconds). Other steps are the same as in Example 2.

[0096] The study found that the lamotrigine tablets prepared in Comparative Example 7 not only had color deviations within the batch, but also increased impurity C from 0% (below the detection limit) to 0.09% in the accelerated stability test after 3 months. In contrast, the lamotrigine tablets prepared in Example 1 showed an increase of 0.01% in impurity C after 3 months. Therefore, the preparation process of Comparative Example 7 has certain quality instability.

[0097] Comparative Example 8 exhibited poor process compliance during preparation, and the wet particles prepared by Comparative Example 2 had unqualified content uniformity (RSD greater than 5%) and poor quality stability.

[0098] Experiment 3: Stability test of influencing factors in Example 2

[0099] The stability of the lamotrigine tablets prepared in Example 2 under influencing conditions was investigated, and the stability test data obtained are shown in Table 5.

[0100] Table 5. Results of the test on influencing factors of lamotrigine tablets prepared in Example 2 (with packaging, specification: 50mg)

[0101]

[0102] Note: 1. "-" indicates that no impurities were detected or the impurity content was below the detection limit and no data was detected; 2. " / " indicates that the item was not detected; 3. The cumulative dissolution of the 0-day sample (dissolution curve in 0.1 mol / L hydrochloric acid solution medium) was 101% after 20 minutes.

[0103] As can be seen from the data in the table above, the lamotrigine tablets prepared in Example 2 were stable after being placed for 30 days under the conditions of light exposure (4500 lx ± 500 lx), high temperature (60 °C), and high humidity (RH 92.5%).

[0104] Experiment 4: Production of Lamotrigine Tablets Process Validation Batch

[0105] Validation production was conducted using the formulation and manufacturing process of Example 2 (repeating Example 2, three consecutive batches). A comprehensive quality comparison study was performed between the validation batch samples and the reference formulation. The validation batch of lamotrigine tablets, with a strength of 50 mg / tablet and a batch size of 200,000 tablets, included the raw materials and excipients as shown in Table 4 by weight. The particle size D90 of the three batches of lamotrigine active pharmaceutical ingredient were 45 μm, 48 μm, and 50 μm, respectively; the particle size D90 of lactose was 98 μm; and the particle size D90 of microcrystalline cellulose was 50 μm.

[0106] The preparation method of lamotrigine tablets is as follows: Figure 1 As shown, the specific preparation process, parameters and production equipment are exactly the same as in Example 2. A total of 3 batches of lamotrigine tablets were prepared. The formulation, process and preparation method of the 3 batches of lamotrigine tablets are completely the same, and the batch numbers are 181208, 181209 and 181210 respectively.

[0107] Experiment 5: Quality stability study of lamotrigine tablets compared to the reference formulation

[0108] The process validation batches of lamotrigine tablets (181208, 181209, 181210) prepared by Experiment 4 were compared with the original imported lamotrigine tablets. Specification: 50mg, batch number PA7P, GlaxoSmithKline Pharmaceuticals S.A.) Quality stability: The stability measurement method is the same as the test method attached above, and the results are shown in Table 6-8 below.

[0109] Table 6. Comparison of process validation batches and reference formulations (long-term trials)

[0110]

[0111] Notes: 1. "-" indicates that the content of impurities was not detected; 2. " / " indicates that the data was not detected; 3. Cumulative dissolution*: This item is the cumulative dissolution of the sample dissolution curve (in 0.1 mol / L hydrochloric acid solution medium) after 20 minutes.

[0112] Table 7 Comparison of process validation batches and reference formulations (intermediate condition tests)

[0113]

[0114] Notes: 1. "-" indicates that the content of impurities was not detected; 2. " / " indicates that the data was not detected; 3. Cumulative dissolution*: This item is the cumulative dissolution of the sample dissolution curve (in 0.1 mol / L hydrochloric acid solution medium) after 20 minutes.

[0115] Table 8. Comparison of process validation batches and reference formulations (accelerated trials)

[0116]

[0117] Notes: 1. "-" indicates that the content of impurities was not detected; 2. " / " indicates that the data was not detected; 3. Cumulative dissolution*: This item is the cumulative dissolution of the sample dissolution curve (in 0.1 mol / L hydrochloric acid solution medium) after 20 minutes.

[0118] After 6 months of accelerated storage (40℃±2℃, RH 75%±5%), the content of impurity C in the reference formulation increased to 0.17%, and the total impurities increased to 0.43%. In the process validation sample, impurity C increased to 0.04%, and the total impurities increased to 0.07%. The quality stability of the validation batch of lamotrigine tablets prepared by this invention is better than that of the reference formulation. After 6 months of accelerated storage, the cumulative dissolution curve of the reference formulation in 0.1 mol / L hydrochloric acid solution showed a 75% cumulative dissolution rate at 20 minutes, with a significant slowing trend in dissolution. The dissolution rate of the process validation samples was greater than 90%, and the properties and content of the process validation samples and the reference formulation showed no significant changes compared to 0 months. This indicates that the quality stability of the validation batch of lamotrigine tablets prepared by this invention is significantly better than that of the reference formulation.

[0119] Under intermediate conditions (30℃±2℃, RH 65%±5%) for 6 months: the content of impurity C in the reference formulation increased to 0.06%, and the total impurities increased to 0.12%; in the process validation sample, impurity C increased slightly, from below the detection limit to 0.01%, still well below the impurity limit (0.5%); other impurities did not increase; there were no significant changes in appearance, dissolution, and content. The quality stability of the validation batch of lamotrigine tablets prepared in this invention is better than that of the reference formulation.

[0120] Under long-term conditions (25℃±2℃, RH 60%±10%) for 6 months: impurity C in the reference formulation increased slightly, no new impurities were generated in the process validation sample, and there were no significant changes in other impurities, dissolution rate, and content. The quality stability of the validation batch of lamotrigine tablets prepared in this invention is better than that of the reference formulation.

[0121] Experiment 6: Comparison of dissolution curve results between validation batch and reference formulation

[0122] Stability tests were conducted on the process validation batch samples (specification: 50mg, batch numbers: 181208, 181209, 181210) and the reference preparation (batch number: PA7P). Dissolution curves were measured at 0 months, accelerated dissolution at 6 months, intermediate dissolution at 6 months, and long-term dissolution at 6 months. The results are shown in Tables 9-12, and some dissolution curve results are shown in […]. Figure 2-8 .

[0123] (1) 0.1 mol / L hydrochloric acid solution

[0124] Table 9 Comparison of dissolution profiles of three batches for reference formulation and process validation (0.1 mol / L hydrochloric acid solution)

[0125]

[0126]

[0127] (2) pH 4.0 acetate buffer

[0128] Table 10 Comparison of dissolution profiles for three batches of the reference formulation and process validation (pH 4.0 acetate buffer)

[0129]

[0130] (3) pH 5.5 phosphate buffer

[0131] Table 11 Comparison of dissolution profiles for three batches of the reference formulation and process validation (pH 5.5 phosphate buffer)

[0132]

[0133] (4) pH 6.8 phosphate buffer

[0134] Table 12 Comparison of dissolution profiles of three batches for reference formulation and process validation (pH 6.8 phosphate buffer)

[0135]

[0136] Under accelerated conditions (40℃±2℃, RH 75%±5%), long-term conditions (25℃±2℃, RH 60%±10%), and intermediate conditions (30℃±2℃, RH 65%±5%), the dissolution curves of the process validation batch samples were relatively stable in all dissolution media after 6 months. The reference formulation showed a significant slowing trend (after 6 months of accelerated dissolution, only 75% dissolved in 0.1 mol / L hydrochloric acid solution after 20 minutes, see...). Figure 2 ); Under long-term and intermediate conditions, there is also a clear trend of slower dissolution, such as Figure 2-8 As shown, the lamotrigine tablets in the validation batch prepared in this invention exhibit better dissolution stability than the reference formulation.

[0137] In summary, the lamotrigine tablets developed in this invention showed good quality stability after 6 months of testing under accelerated conditions (40℃±2℃, RH75%±5%), long-term conditions (25℃±2℃, RH60%±10%), and intermediate conditions (30℃±2℃, RH65%±5%). The growth rate of impurity C was significantly slower than that of the reference formulation, and the dissolution trend was also significantly slower, indicating that the lamotrigine tablets developed in this invention have better quality stability.

[0138] Those skilled in the art should understand that the discussion of any of the above embodiments is merely exemplary and is not intended to imply that the scope of protection of this application is limited to these examples; within the framework of this application, the technical features of the above embodiments or different embodiments can also be combined, the steps can be implemented in any order, and there are many other variations of different aspects of one or more embodiments of this application as described above, which are not provided in detail for the sake of brevity.

Claims

1. A lamotrigine formulation composition, characterized in that, The raw materials include the following components by weight: 50 parts lamotrigine, 47 parts lactose, 55 parts microcrystalline cellulose, 4 parts sodium carboxymethyl starch, 2.5 parts povidone K30, 1 part magnesium stearate, and 0.1 parts yellow iron oxide; the particle size D90 of lamotrigine is 47 μm ± 5 μm, the particle size D90 of lactose is 95-98 μm, and the particle size D90 of microcrystalline cellulose is 49-50 μm. The preparation method of the lamotrigine formulation composition is as follows: premixing the colorant mixture and the active ingredient mixture, granulating, drying, sizing, total mixing, and tableting to obtain the lamotrigine formulation composition; the colorant mixture is a mixture of lactose and yellow iron oxide after co-sieving; the active ingredient mixture is a mixture of lamotrigine, residual lactose, microcrystalline cellulose, and sodium carboxymethyl starch; during the granulation operation, a povidone K30 aqueous solution and water are added sequentially as binders; after drying and sizing the obtained wet granules, magnesium stearate of the prescribed amount is added for total mixing, and the mixed material is tableted to obtain the lamotrigine formulation composition.

2. The lamotrigine formulation composition according to claim 1, characterized in that, The weight ratio of lamotrigine, lactose, and microcrystalline cellulose is 50:47:

55. The particle size D90 of lamotrigine is 45μm, 47μm, 48μm, or 50μm, the particle size D90 of lactose is 95μm or 98μm, and the particle size D90 of microcrystalline cellulose is 49μm or 50μm.

3. The lamotrigine formulation composition according to claim 1, characterized in that, In the colorant mixture, the weight ratio of lactose to yellow iron oxide is 100:

1.

4. The lamotrigine formulation composition according to claim 1, characterized in that, During the granulation process, a povidone K30 aqueous solution and water are added sequentially within 60 seconds as a binder.

5. The lamotrigine formulation composition according to claim 1, characterized in that, The weight concentration of the polyvinylpyrrolidone K30 aqueous solution is 5%, and the weight ratio of the polyvinylpyrrolidone K30 aqueous solution to water is 10:0.5 to 2.

6. The lamotrigine formulation composition according to claim 1, characterized in that, The colorant mixture is passed through a 60-mesh sieve, the stirring speed of the granulation is 170 rpm ± 5%, the shearing speed is 1500 rpm ± 5%, and the wet granules after granulation are passed through a 16-mesh sieve.

7. The lamotrigine formulation composition according to claim 6, characterized in that, The wet granules after granulation are dried at a temperature of 60-70°C, and the material is collected when the moisture content of the granules is controlled at 1.0%-4.0%.

8. The lamotrigine formulation composition according to claim 1, characterized in that, The mixing process involves adding the prescribed amount of magnesium stearate for mixing, with a mixing speed of 10 r / min and a mixing time of 5 minutes.

9. The lamotrigine formulation composition according to claim 1, characterized in that, The tablet weight of the lamotrigine formulation composition is 0.16g / tablet, and the hardness of the lamotrigine formulation composition tablets is 2kg to 5kg.

10. A method for preparing a lamotrigine formulation composition according to any one of claims 1-9, characterized in that, The colorant mixture and the active ingredient mixture are premixed, granulated, dried, sized, fully mixed, and tableted to obtain a lamotrigine formulation composition. The colorant mixture is a mixture of lactose and yellow iron oxide after co-sieving. The active ingredient mixture is a mixture of lamotrigine, residual lactose, microcrystalline cellulose, and sodium carboxymethyl starch. During the granulation operation, a povidone K30 aqueous solution and water are added sequentially as binders. After drying and sizing, the obtained wet granules are fully mixed with the prescribed amount of magnesium stearate. The mixed material is then tableted to obtain the lamotrigine formulation composition.

Images