Pregabalin capsule and preparation process thereof

Abstract

The invention discloses a pregabalin capsule which comprises the following raw materials in parts by weight: 7-9 parts of pregabalin, 12-21.6 parts of a filling agent, 0.5-1.5 parts of a lubricating agent and 90-110 parts of a gelatin hollow capsule, wherein the filling agent is a mixture of acetylated corn starch and lipidosome coated lactose. The pregabalin capsule is used for solving the technical problem that the stability of the pregabalin capsule is poor.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, and particularly relates to a pregabalin capsule and its preparation process. Background Technology

[0002] Pregabalin is a non-γ-aminobutyric acid receptor agonist or antagonist, a novel calcium channel modulator that blocks voltage-dependent calcium channels, reducing neurotransmitter release. Clinically, it is primarily used for neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, and as an adjunct therapy for partial seizures, generalized anxiety disorders, central nervous system pain (including neuropathic pain associated with spinal cord injury, stroke, and multiple sclerosis), and fibromyalgia.

[0003] Because pregabalin contains primary amino and carboxyl groups, it is prone to intramolecular condensation to produce lactam, especially under humid and hot conditions. Furthermore, the primary amino group in pregabalin is also prone to Maillard reaction with the carboxyl group in lactose molecules under humid and hot conditions, resulting in poor stability of pregabalin capsules and affecting their use. Summary of the Invention

[0004] This invention provides a pregabalin capsule and its preparation process to solve the technical problem of poor stability of existing pregabalin capsules.

[0005] In view of this, the present invention provides a pregabalin capsule comprising the following raw materials in parts by weight: 7-9 parts pregabalin, 12-21.6 parts filler, 0.5-1.5 parts lubricant, and 90-110 parts gelatin empty capsules, wherein the filler is a mixture of acetylated corn starch and liposome-coated lactose.

[0006] Optionally, the weight ratio of the acetylated corn starch and the liposome-coated lactose is (0.5-0.8):1.

[0007] Optionally, the acetylated corn starch is prepared by the following method: corn starch is placed in water, mixed evenly to obtain a suspension, acetic anhydride and catalyst are added, the mixture is heated to a higher temperature, and the reaction is carried out. After the reaction is completed, sodium hydroxide solution is added, the mixture is mixed evenly, filtered, the product is collected, washed, and dried to obtain acetylated corn starch.

[0008] Furthermore, the acetylated corn starch is prepared by the following method: corn starch is placed in water, mixed evenly to obtain a suspension, acetic anhydride and catalyst are added, the temperature is heated to 30-50℃, and the reaction is carried out for 1-4 hours. After the reaction is completed, a 40% sodium hydroxide solution is added, mixed evenly, filtered, the product is taken, washed with water until neutral, and dried to obtain acetylated corn starch.

[0009] The amount of water added per 1g of corn starch is 10-20mL, the catalyst is pyridine, the weight ratio of corn starch to catalyst is 1:(0.01-0.03), and the amount of sodium hydroxide solution added per 1g of corn starch is 1-3mL.

[0010] Optionally, the weight ratio of corn starch to acetic anhydride is 1:(0.1-0.3).

[0011] Optionally, the liposome-coated lactose is prepared using the following method:

[0012] A1: Phospholipids and cholesterol are placed in chloroform, mixed evenly, and evaporated by rotary evaporation to obtain a lipid film; lactose is placed in water, mixed evenly, to obtain a lactose solution;

[0013] A2: Add lactose solution to the lipid membrane, sonicate under water bath conditions, filter with a microporous membrane, and then freeze-dry to obtain liposome-coated lactose.

[0014] Furthermore, the liposome-coated lactose is prepared using the following method:

[0015] A1: Phospholipids and cholesterol are placed in chloroform, mixed evenly, and evaporated by rotary evaporation to obtain a lipid film; lactose is placed in water, mixed evenly, to obtain a lactose solution;

[0016] A2: Add lactose solution to the lipid membrane, sonicate for 5-10 min in a water bath at 40-60℃ with an ultrasonic power of 100-200w, filter through a 0.22-0.45μm microporous membrane, and then freeze-dry to obtain liposome-coated lactose.

[0017] The amount of chloroform added per 1g of total weight of phospholipids and cholesterol is 8-12mL, and the amount of water added per 1g of lactose is 10-20mL.

[0018] Optionally, the weight ratio of lactose, phospholipids and cholesterol is 1:(5-8):(1-2).

[0019] Optionally, the lubricant is either talc or magnesium stearate.

[0020] Furthermore, the lubricant is talc.

[0021] A preparation process for pregabalin capsules includes the following steps:

[0022] S1: Material preparation: Weigh out the filler, lubricant and pregabalin according to the requisition quantity in the batch production order;

[0023] S2: Raw material pretreatment: Sieve pregabalin, filler, and lubricant separately, and then weigh them according to the prescription amount;

[0024] S3: Total Mixing: The weighed prescription amounts of pregabalin, filler, and lubricant are mixed together. After mixing, the pregabalin capsule intermediate is obtained and tested.

[0025] S4: Capsule filling: using pregabalin capsule intermediates to fill gelatin hollow capsules;

[0026] S5: Aluminum-plastic inner packaging: The filled capsules are packaged in aluminum-plastic packaging, and QA samples are taken and sent for full inspection. After outer packaging, they are put into storage if they pass the inspection.

[0027] Furthermore, a preparation process for pregabalin capsules includes the following steps:

[0028] S1: Material preparation: Weigh out the filler, lubricant and pregabalin according to the requisition quantity in the batch production order;

[0029] S2: Raw material pretreatment:

[0030] Raw material sieving: Manually sieve the required amount of pregabalin through a 70-90 mesh stainless steel sieve. After sieving, take a sample for particle size and particle size distribution testing. The particle size and particle size distribution of the sieved pregabalin should be controlled within the following ranges: D50: 10-355μm, D90: <938μm. Raw materials that fail to pass through the 70-90 mesh stainless steel sieve should be disposed of as non-recyclable materials.

[0031] Sieving of excipients: Pass the required amount of filler and lubricant through an 80-100 mesh sieve. Excipients that fail to pass through the 80-100 mesh sieve shall be disposed of as non-recyclable.

[0032] Weigh the pretreated filler and lubricant according to the prescription amount. After receiving the report on the particle size and particle size distribution of pregabalin and finding that it meets the requirements, weigh the pregabalin according to the prescription amount.

[0033] The remaining auxiliary materials after feeding are not recyclable, and the remaining raw materials are returned to the warehouse.

[0034] S3: Total Mixing: Set the mixing frequency to 15-16.5Hz and the mixing time to 8-12min. Add the weighed prescription amounts of pregabalin, filler, and lubricant to the multi-directional JSH-60B motion mixer in sequence. After mixing, the pregabalin capsule intermediate (total mixed powder) is obtained. QA samples of the pregabalin capsule intermediate (total mixed powder) are sent for testing of its properties and content. The shelf life of the pregabalin capsule intermediate (total mixed powder) is 30 days.

[0035] The overall mixing process yield is ≥97.0%, and the material balance rate is 98.0%~103.0%.

[0036] S4: Capsule Filling: Calculate the center fill weight of the contents according to the content in the inspection report of pregabalin capsule intermediate (total mixed powder), then calculate the content fill weight range. Calculate the center fill weight and the content fill weight range of the capsules based on the average capsule weight in the inspection report of gelatin empty capsules. Collect the inspected and qualified pregabalin capsule intermediate (total mixed powder) and gelatin empty capsules from the intermediate station according to the batch production order for the capsule filling process, and verify the material name, specifications, batch number, and quantity. The NJP-400A fully automatic hard capsule filling machine has a filling rod specification of #4. Operate according to the equipment SOP, add the gelatin empty capsules to the hopper, start the machine to begin empty capsule trial operation, observe that the capsule extraction and locking are qualified, add the pregabalin capsule intermediate (total mixed powder) to the hopper, and perform a trial filling according to the content fill weight range, adjusting the filling... The filling volume variation is controlled within ±5%. After successful trial filling and verification by workshop management and QA, the capsule filling machine is set to a production speed range of 200-300 capsules / min for formal filling. The production speed is recorded at the start of filling, every 20 minutes of filling, before restarting after a stop, and near the end of filling. 60 capsules are taken to check their weight, and their appearance is constantly checked. The capsules should be free of contamination, spots, and powder leakage. During filling, the qualified pregabalin capsule intermediate (capsules) are placed in a CYJ-150 capsule / tablet polishing machine. Following the equipment's SOP, the speed is set to 5-7 to polish the capsules (achieving a bright, powder-free surface). The shelf life of the pregabalin capsule intermediate (capsules) is 30 days.

[0037] The capsule filling process yield is ≥95.0%, and the material balance rate is 90.0%~102.0%.

[0038] S5: Aluminum-plastic inner packaging: Set the upper temperature to 120±5℃ (control range 110℃~130℃), the lower temperature to 120±5℃ (control range 120℃~140℃), the heat sealing temperature to 160±5℃ (control range 140℃~160℃), the batch number temperature to 105±5℃ (control range 100℃~125℃), the main unit frequency to 30~40Hz (control range 25~40Hz), and the traction length to 96.00mm. Preheat the flat blister packaging machine. After the required temperature is reached, start the machine for trial operation without adding pregabalin capsule intermediates (capsules). After inspecting the appearance, vacuum leak test (empty plate), product batch number, and expiration date of the aluminum-plastic composite blank sheet, and confirming they meet the requirements, add the pregabalin capsule intermediate (capsule) into the hopper to begin trial inner packaging. Notify workshop management and QA to check and verify that the product batch number and expiration date are printed correctly, clearly, without skewing or inversion, and that the airtightness is good. After passing the inspection, production begins. Record the upper temperature, lower temperature, heat-sealing temperature, batch number temperature, and main unit frequency once at the start of aluminum-plastic packaging, every 20 minutes of cumulative aluminum-plastic packaging, before restarting aluminum-plastic packaging after a machine stop, and near the end of aluminum-plastic packaging. After the aluminum-plastic inner packaging is completed, QA takes samples for full inspection.

[0039] Vacuum leak detection: Use a C-955 sealing tester to test every 35 minutes. Take 8 panels produced side by side each time, control the vacuum degree to -51kpa to -55kpa and maintain it for 1 minute. If the aluminum composite panel is confirmed to have good airtightness (no air leakage), production can continue. If there is poor airtightness, the machine should be stopped immediately to find out the cause and adjust the equipment until the airtightness is good.

[0040] Panel Inspection: During production, pay attention to the appearance of the aluminum-plastic composite panels. They should be well heat-sealed, with uniform and clear embossing, round and even bubble holes, and flat cuts. Otherwise, the machine should be stopped, and the cause should be investigated before production can continue. During the inspection, unqualified aluminum-plastic composite panels should be removed. Aluminum-plastic composite panels with poor sealing, aluminum foil wrinkles, broken bubble holes, etc., which do not affect the appearance quality of the capsules, can be used to remove the capsules and recycle them. Aluminum-plastic composite panels with leaks, lumps, or crushing, which affect the appearance quality of the capsules, should be treated as unqualified products. The shelf life of pregabalin capsule semi-finished products (aluminum-plastic composite panels) is 90 days.

[0041] The yield of the aluminum-plastic inner packaging process is ≥96.0%, and the material balance rate is 97.0%~103.0%.

[0042] All the above operations are performed in a Class D clean area. The following operations are performed in a general area. Before the outer packaging operation begins, a thorough cleaning and re-inspection should be conducted. After verification and confirmation, outer packaging materials should be collected according to the batch packaging instruction sheet. The production date, product batch number, and expiration date should be printed on the packaging materials. After QA verifies and signs, a sample should be printed and attached to the packaging record. If packaging is not done in time, the corresponding status label should be made.

[0043] The yield of the outer packaging process is ≥97.0%, and the material balance rate is 97.0%~103.0%;

[0044] Finished product yield: ≥89.0%, total material balance rate: 98.0%~101.05%.

[0045] As can be seen from the above technical solutions, the embodiments of the present invention have the following advantages:

[0046] 1. This invention utilizes acetylated corn starch and liposome-coated lactose as fillers, significantly improving the stability of pregabalin capsules. Acetylated corn starch forms a stable matrix network within the capsule, reducing direct contact between pregabalin and the external environment through physical encapsulation, thereby lowering the risk of oxidation and hygroscopic degradation. Furthermore, acetylation replaces the hydroxyl groups in the starch molecular chain with acetyl groups, weakening intermolecular hydrogen bonding and reducing starch aging or crystallization caused by hygroscopicity, thus preventing clumping or stratification within the capsule and contributing to improved stability. Liposome-coated lactose not only controls the lactose release rate and reduces the localized high osmotic pressure environment caused by rapid lactose hydrolysis, inhibiting the chemical degradation of pregabalin, but also reduces lactam impurities generated by pregabalin oxidation, further enhancing stability. Through the synergistic effect of these two components, acetylated corn starch forms a primary physical barrier, while liposome-coated lactose acts as a secondary isolation layer, constructing a dual-protection system that significantly improves the stability of pregabalin. Detailed Implementation

[0047] To enable those skilled in the art to better understand the present invention, the technical solutions in the embodiments of the present invention are clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Unless otherwise specified, all raw materials, reagents, instruments, and equipment used in the present invention can be purchased on the market or prepared by existing methods.

[0048] Preparation Example

[0049] Preparation Example 1

[0050] An acetylated corn starch is prepared by the following method:

[0051] 1 kg of corn starch was placed in 15 L of water and mixed evenly to obtain a suspension. 100 g of acetic anhydride and 20 g of pyridine were added, and the mixture was heated to 40 °C and reacted for 2 h. After the reaction was completed, 2 L of 40% sodium hydroxide solution was added, mixed evenly, filtered, and the product was taken. The product was washed with water until neutral and dried to obtain acetylated corn starch.

[0052] Preparation Example 2

[0053] An acetylated corn starch differs from Preparation Example 1 in that the amount of acetic anhydride added is different; in Preparation Example 2, the amount of acetic anhydride added is 200g.

[0054] Preparation Example 3

[0055] An acetylated corn starch differs from Preparation Example 1 in that the amount of acetic anhydride added is different; in Preparation Example 3, the amount of acetic anhydride added is 300g.

[0056] Preparation Example 4

[0057] A liposome-coated lactose is prepared by the following method:

[0058] A1: Add 5 kg of phospholipids and 1 kg of cholesterol to 60 L of chloroform, mix well, and evaporate by rotary evaporation to obtain a lipid film; add 1 kg of lactose to 15 L of water, mix well, and obtain a lactose solution.

[0059] A2: Add lactose solution to the lipid membrane, sonicate for 8 min at 50°C with an ultrasonic power of 150 W, filter through a 0.3 μm microporous membrane, and then freeze-dry to obtain liposomes coated with lactose.

[0060] Preparation Example 5

[0061] A liposome-coated lactose differs from Preparation Example 4 in that the amount of phospholipid added is different; in Preparation Example 5, the amount of phospholipid added is 6.5 kg.

[0062] Preparation Example 6

[0063] A liposome-coated lactose differs from Preparation Example 4 in that the amount of phospholipid added is different; in Preparation Example 6, the amount of phospholipid added is 8 kg.

[0064] Preparation Example 7

[0065] A liposome-coated lactose differs from Preparation Example 5 in that the amount of cholesterol added is different; in Preparation Example 7, the amount of cholesterol added is 1.5 kg.

[0066] Preparation Example 8

[0067] A liposome-coated lactose differs from Preparation Example 5 in that the amount of cholesterol added is different; in Preparation Example 8, the amount of cholesterol added is 2 kg.

[0068] Example

[0069] Example 1

[0070] A pregabalin capsule, the proportions of its raw materials are shown in Table 1.

[0071] A process for preparing pregabalin capsules includes the following steps: acetylated corn starch is prepared using Preparation Example 1, and liposome-coated lactose is prepared using Preparation Example 4.

[0072] S1: Material preparation: Weigh out the filler, lubricant and pregabalin according to the requisition quantity in the batch production order;

[0073] S2: Raw material pretreatment:

[0074] Raw material sieving: Manually pass the required amount of pregabalin through an 80-mesh stainless steel sieve. After sieving, take a sample for particle size and particle size distribution testing. The particle size and particle size distribution of the sieved pregabalin should be controlled within the following ranges: D50: 10-355μm, D90: <938μm. Raw materials that fail to pass through the 80-mesh stainless steel sieve should be disposed of as non-recyclable materials.

[0075] Sieving of excipients: Pass the required amount of filler and lubricant through a 90-mesh sieve. Excipients that fail to pass through the 90-mesh sieve shall be disposed of as non-recyclable.

[0076] Weigh the pretreated filler and lubricant according to the prescription amount. After receiving the report on the particle size and particle size distribution of pregabalin and finding that it meets the requirements, weigh the pregabalin according to the prescription amount.

[0077] The remaining auxiliary materials after feeding are not recyclable, and the remaining raw materials are returned to the warehouse.

[0078] S3: Total Mixing: Set the mixing frequency to 16Hz and the mixing time to 10min. Add the weighed prescription amounts of pregabalin, filler, and lubricant to the multi-directional JSH-60B motion mixer in sequence. After mixing, the pregabalin capsule intermediate (total mixed powder) is obtained. QA samples of the pregabalin capsule intermediate (total mixed powder) are sent for testing of its properties and content. The shelf life of the pregabalin capsule intermediate (total mixed powder) is 30 days.

[0079] The overall mixing process yield is ≥97.0%, and the material balance rate is 100%.

[0080] S4: Capsule Filling: Calculate the center weight of contents according to the content in the pregabalin capsule intermediate (total powder) inspection report, then calculate the content weight range. Calculate the center weight and the weight range of contents based on the average capsule weight in the gelatin empty capsule inspection report. Collect the inspected and qualified pregabalin capsule intermediate (total powder) and gelatin empty capsules from the intermediate station according to the batch production order for the capsule filling process, and verify the material name, specifications, batch number, and quantity. The NJP-400A fully automatic hard capsule filling machine has a filling rod specification of #4. Operate according to the equipment SOP, add the gelatin empty capsules to the hopper, start the machine to begin empty capsule trial operation, and observe that the capsule extraction and locking are qualified. Then add the pregabalin capsule intermediate (total powder) to the hopper and perform a trial filling according to the content weight range. Adjust the filling rod to control the content volume difference to ±5%. After successful trial filling and verification by workshop management and QA, set the capsule filling machine's production speed to 250 capsules / min for formal filling. Record the production speed at the start of filling, every 20 minutes of filling, before restarting after a stop, and near the end of filling. Take 60 capsules to check their weight and check their appearance regularly. The capsules should be free of contamination, spots, and powder leakage. During filling, place the qualified pregabalin capsule intermediate (capsules) in a CYJ-150 capsule / tablet polishing machine and operate according to the equipment's SOP, setting the speed to 6 to polish the capsules (achieving a bright, powder-free surface). The shelf life of the pregabalin capsule intermediate (capsules) is 30 days.

[0081] The capsule filling process yield is ≥95.0%, and the material balance rate is 98.0%.

[0082] S5: Aluminum-plastic inner packaging: Set the upper temperature to 125℃, the lower temperature to 130℃, the heat sealing temperature to 150℃, the batch number temperature to 110℃, the main unit frequency to 35Hz, and the traction length to 96.00mm. Preheat the flat blister packaging machine. After the required temperature is reached, start the machine to test the aluminum-plastic empty blister packaging without adding pregabalin capsule intermediates (capsules). Check that the appearance, vacuum leak test (empty blister), product batch number, and expiration date all meet the requirements. Then, add the pregabalin capsules. The intermediate (capsule) is added to the hopper, and trial inner packaging begins. Workshop management and QA are notified to check and verify that the product batch number and expiration date are printed correctly, clearly, without skewing or inversion, and with good airtightness. After passing the inspection, production begins. The upper temperature, lower temperature, heat sealing temperature, batch number temperature, and main unit frequency are recorded once when aluminum-plastic packaging begins, every 20 minutes of aluminum-plastic packaging, before restarting aluminum-plastic packaging after a machine stop, and near the end of aluminum-plastic packaging. After the aluminum-plastic inner packaging is completed, QA takes samples for full inspection.

[0083] Vacuum leak detection: Use a C-955 sealing tester to test every 35 minutes. Take 8 panels produced side by side each time, control the vacuum degree at -53kpa and maintain it for 1 minute. If the aluminum composite panel is confirmed to have good airtightness (no air leakage), production can continue. If there is poor airtightness, the machine should be stopped immediately to find out the cause and adjust the equipment until the airtightness is good.

[0084] Panel Inspection: During production, pay attention to the appearance of the aluminum-plastic composite panels. They should be well heat-sealed, with uniform and clear embossing, round and even bubble holes, and flat cuts. Otherwise, the machine should be stopped, and the cause should be investigated before production can continue. During the inspection, unqualified aluminum-plastic composite panels should be removed. Aluminum-plastic composite panels with poor sealing, aluminum foil wrinkles, broken bubble holes, etc., which do not affect the appearance quality of the capsules, can be used to remove the capsules and recycle them. Aluminum-plastic composite panels with leaks, lumps, or crushing, which affect the appearance quality of the capsules, should be treated as unqualified products. The shelf life of pregabalin capsule semi-finished products (aluminum-plastic composite panels) is 90 days.

[0085] The yield of the aluminum-plastic inner packaging process is ≥96.0%, and the material balance rate is 99.0%.

[0086] All the above operations are performed in a Class D clean area. The following operations are performed in a general area. Before the outer packaging operation begins, a thorough cleaning and re-inspection should be conducted. After verification and confirmation, outer packaging materials should be collected according to the batch packaging instruction sheet. The production date, product batch number, and expiration date should be printed on the packaging materials. After QA verifies and signs, a sample should be printed and attached to the packaging record. If packaging is not done in time, the corresponding status label should be made.

[0087] The yield rate of the outer packaging process is ≥97.0%, and the material balance rate is 99.0%.

[0088] Finished product yield: ≥89.0%, total material balance rate: 100.05%.

[0089] Examples 2-7

[0090] A pregabalin capsule differs from Example 1 in that the raw material ratio of the pregabalin capsule is different, as shown in Table 1.

[0091] Table 1. Weight of each ingredient in pregabalin capsules (kg)

[0092]

[0093] Example 8

[0094] A pregabalin capsule differs from Example 6 in that the acetylated corn starch in the filler is derived from a different source, being prepared using Preparation Example 2.

[0095] Example 9

[0096] A pregabalin capsule differs from Example 6 in that the acetylated corn starch in the filler is derived from a different source, being prepared using Preparation Example 3.

[0097] Example 10

[0098] A pregabalin capsule differs from Example 8 in that the source of the liposome-coated lactose in the filler is different; it was prepared using Preparation Example 5.

[0099] Example 11

[0100] A pregabalin capsule differs from Example 8 in that the source of the liposome-coated lactose in the filler is different; it was prepared using Preparation Example 6.

[0101] Example 12

[0102] A pregabalin capsule differs from Example 8 in that the source of the liposome-coated lactose in the filler is different; it was prepared using Preparation Example 7.

[0103] Example 13

[0104] A pregabalin capsule differs from Example 8 in that the source of the liposome-coated lactose in the filler is different; it was prepared using Preparation Example 8.

[0105] Comparative Example

[0106] Comparative Example 1

[0107] A pregabalin capsule differs from Example 1 in that the acetylated corn starch in the filler is replaced in equal amounts with liposome-coated lactose.

[0108] Comparative Example 2

[0109] A pregabalin capsule differs from Example 1 in that the liposome-coated lactose in the filler is replaced in equal amounts with acetylated corn starch.

[0110] Comparative Example 3

[0111] A pregabalin capsule differs from Example 1 in that the acetylated corn starch in the filler is replaced with an equal amount of corn starch.

[0112] Comparative Example 4

[0113] A pregabalin capsule differs from Example 1 in that the liposome-coated lactose in the filler is replaced with an equal amount of lactose.

[0114] Comparative Example 5

[0115] A pregabalin capsule differs from Example 1 in that the acetylated corn starch in the filler is replaced with an equal amount of corn starch, and the liposome-coated lactose is replaced with an equal amount of lactose.

[0116] Performance testing

[0117] The pregabalin capsules in Examples 1-13 and Comparative Examples 1-5 were subjected to the following tests:

[0118] Stability: Pregabalin capsules were kept at 40℃ / RH75% and samples were taken at 0, 30, 60 and 90 days. The stability of the capsules was determined according to the Chinese Pharmacopoeia 2020 edition. The test results are shown in Table 2.

[0119] Table 2 Detection Results

[0120]

[0121] As can be seen from Table 2, the pregabalin capsules of the present invention significantly improve the stability of pregabalin capsules through the synergistic effect between the raw materials. Specifically, the single impurity content of the 30-day pregabalin capsules is 0.81-1.14 and the total impurity content is 1.15-1.41, the single impurity content of the 60-day pregabalin capsules is 1.36-1.60 and the total impurity content is 1.87-2.15, and the single impurity content of the 90-day pregabalin capsules is 2.09-2.31 and the total impurity content is 2.75-2.99.

[0122] Combining Example 1 and Comparative Examples 1-5, it can be seen that in Example 1, the single impurity content in the 30-day pregabalin capsules was 1.14 and the total impurity content was 1.41; in Example 1, the single impurity content was 1.60 and the total impurity content was 2.15; and in Example 1, the single impurity content was 2.31 and the total impurity content was 2.99, which is better than that in Comparative Examples 1-5. This indicates that using acetylated corn starch and liposome-coated lactose as fillers is more suitable. Through the synergistic effect between the two, acetylated corn starch forms a primary physical barrier, and liposome-coated lactose acts as a secondary isolation layer, constructing a dual protection system that can improve the stability of pregabalin.

[0123] As can be seen from Examples 1-7, the single impurity content of the pregabalin capsules in Example 6 for 30 days is 0.93 and the total impurity content is 1.29, for 60 days it is 1.47 and the total impurity content is 1.99, and for 90 days it is 2.20 and the total impurity content is 2.87, which is better than other examples. This indicates that the amount of each raw material added in Example 6 is more appropriate and can better improve the stability of the pregabalin capsules.

[0124] As can be seen from Examples 6 and 8-9, the single impurity content of the pregabalin capsules in Example 8 for 30 days was 0.89 and the total impurity content was 1.25, for 60 days it was 1.43 and the total impurity content was 1.95, and for 90 days it was 2.17 and the total impurity content was 2.83, which is better than other examples. This indicates that the acetylated corn starch prepared by Preparation Example 2 is more suitable, which also indicates that the amount of acetic anhydride added in Preparation Example 2 is more appropriate. If the amount of acetic anhydride added is too small, it will not play a better role. If the amount of acetic anhydride added is too large, it will easily cause side reactions, impurities or by-products, which will reduce the purity of the acetylated corn starch and affect the function of the acetylated corn starch, thus affecting the stability of the pregabalin capsules.

[0125] As can be seen from Examples 8 and 10-13, the single impurity content of the pregabalin capsules in Example 12 was 0.81 for 30 days and 1.15 for total impurities; 1.36 for 60 days and 1.87 for total impurities; and 2.09 for 90 days and 2.75 for total impurities. This indicates that the liposome-coated lactose prepared in Example 7 was more suitable for Example 12. It also indicates that the amount of phospholipids and cholesterol added in Example 7 was more appropriate. Too little addition would not have a better effect; too much addition would destroy the bilayer space, causing micelle rupture and uneven dispersion, thus affecting the effect of the pregabalin capsules.

[0126] The above-described embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A pregabalin capsule, characterized in that: It comprises the following raw materials in parts by weight: 7-9 parts pregabalin, 12-21.6 parts filler, 0.5-1.5 parts lubricant, and 90-110 parts gelatin empty capsules, wherein the filler is a mixture of acetylated corn starch and liposome-coated lactose.

2. The pregabalin capsule according to claim 1, characterized in that: The weight ratio of the acetylated corn starch to the liposome-coated lactose is (0.5-0.8):

1.

3. The pregabalin capsule according to claim 1, characterized in that: The acetylated corn starch is prepared by the following method: corn starch is placed in water and mixed evenly to obtain a suspension. Acetic anhydride and catalyst are added, and the mixture is heated to allow the reaction to proceed. After the reaction is completed, sodium hydroxide solution is added, the mixture is mixed evenly, filtered, and the product is collected, washed, and dried to obtain acetylated corn starch.

4. The pregabalin capsule according to claim 3, characterized in that: The weight ratio of corn starch to acetic anhydride is 1:(0.1-0.3).

5. The pregabalin capsule according to claim 1, characterized in that: The liposome-coated lactose was prepared using the following method: A1: Phospholipids and cholesterol are placed in chloroform, mixed evenly, and evaporated by rotary evaporation to obtain a lipid film; lactose is placed in water, mixed evenly, to obtain a lactose solution; A2: Add lactose solution to the lipid membrane, sonicate under water bath conditions, filter with a microporous membrane, and then freeze-dry to obtain liposome-coated lactose.

6. The pregabalin capsule according to claim 5, characterized in that: The weight ratio of lactose, phospholipids and cholesterol is 1:(5-8):(1-2).

7. The pregabalin capsule according to claim 1, characterized in that: The lubricant is either talc or magnesium stearate.

8. A preparation process for pregabalin capsules as described in claims 1-7, characterized in that: Includes the following steps: S1: Material preparation: Weigh out the filler, lubricant and pregabalin according to the requisition quantity in the batch production order; S2: Raw material pretreatment: Sieve pregabalin, filler, and lubricant separately, and then weigh them according to the prescription amount; S3: Total Mixing: The weighed prescription amounts of pregabalin, filler, and lubricant are mixed together. After mixing, the pregabalin capsule intermediate is obtained and tested. S4: Capsule filling: using pregabalin capsule intermediates to fill gelatin hollow capsules; S5: Aluminum-plastic inner packaging: The filled capsules are packaged in aluminum-plastic packaging, and QA samples are taken and sent for full inspection. After outer packaging, they are put into storage if they pass the inspection.

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