Pharmaceutical composition containing perampanel

Abstract

The present invention provides a pharmaceutical composition containing perampanel, which comprises perampanel of a specified particle size and a specific prescription, and can better prevent perampanel from agglomerating into fine granular substances during granulation and drying, and ensure that the main drug is evenly dispersed in the pharmaceutical composition. At the same time, the preparation process is improved, the reproducibility is good, and the preparation is more stable.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a pharmaceutical composition containing perampanel. Background Art

[0002] Perampanel tablets are a kind of drug with AMPA receptor antagonism and / or kainate receptor blocking effect, suitable for use as a therapeutic or preventive agent for neurodegenerative diseases, etc. Its chemical name is 2-(6′-oxo-1′-phenyl-1′,6′-dihydro[2,3′-bipyridine]-5′-yl)-benzonitrile hydrate (4:3), and its structural formula is as follows:

[0003]

[0004] The FDA announced that Perampanel tablets (trade name: Fycompa ® ) pointed out in the chemical review that Perampanel has polymorphs, including 5 anhydrates and 1 hydrate (3 / 4 hydrate), and the API is controlled to be 3 / 4 hydrate. 3 / 4 hydrate and anhydrate are easily converted into each other. At 60°C, 3 / 4 hydrate can be converted into anhydrate in a short time. During the preparation of the drug composition, due to heat, it is very easy to cause crystal conversion, and the quality stability of the drug cannot be guaranteed. The compound patent 200580011565.9 discloses the prescription and conventional preparation process of Perampanel tablets.

[0005] Perampanel is a BCS II poorly soluble drug with a small tablet size. The main drug accounts for only 2% of the drug composition and is not easy to disperse evenly. The preparation process is a wet granulation process. During the preparation of the drug composition, it is easy to re-agglomerate into fine granular substances during granulation and drying, affecting the uniformity of the preparation content. Therefore, it is necessary to study a new composition with good dispersion and high stability. Summary of the invention

[0006] The present invention provides a pharmaceutical composition containing perampanel, which comprises perampanel of a specified particle size and a specific prescription, and can better prevent perampanel from agglomerating into fine granular substances during granulation and drying, and ensure that the main drug is evenly dispersed in the pharmaceutical composition. At the same time, the preparation process is improved, the reproducibility is good, and the preparation is more stable.

[0007] The present invention provides a pharmaceutical composition containing perampanel, comprising the following ingredients: an active ingredient perampanel, a filler, a disintegrant, a binder, a lubricant, and a dispersant. 90 The particle size is 20~120μm, preferably 40~90μm.

[0008] The filler is selected from one or more of lactose, mannitol, erythritol, pregelatinized starch, microcrystalline cellulose, dextrin, and sorbitol, preferably one or more of lactose, mannitol, and erythritol, more preferably lactose, wherein the lactose preferably has a particle size of 200 mesh.

[0009] The disintegrant is selected from one or more of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and cross-linked polyvinylpyrrolidone, preferably low-substituted hydroxypropyl cellulose and cross-linked sodium carboxymethyl cellulose, and more preferably low-substituted hydroxypropyl cellulose.

[0010] The adhesive is selected from one or more of hydroxypropyl cellulose, povidone, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, starch slurry, and syrup, preferably one or more of hydroxypropyl cellulose, povidone, and hydroxypropyl methylcellulose, more preferably povidone, wherein the povidone is preferably K30 model.

[0011] The lubricant is selected from one or more of stearic acid, magnesium stearate, sodium stearyl fumarate, and glyceryl behenate, preferably one or more of stearic acid, magnesium stearate, and sodium stearyl fumarate, and more preferably magnesium stearate.

[0012] The dispersant is selected from one or more of medium chain triglycerides, glycerol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and polysorbate, preferably medium chain triglycerides and glycerol, and more preferably medium chain triglycerides.

[0013] The present invention provides a pharmaceutical tablet composition of perampanel tablets, comprising the following components:

[0014] (1) 2-4% by weight of perampanel based on dry weight;

[0015] (2) 60 to 90% by weight of a filler, based on dry weight;

[0016] (3) 10 to 20% by weight of a disintegrant based on dry weight;

[0017] (4) 0 to 10% by weight of a binder, calculated on a dry weight basis;

[0018] (5) 0 to 0.5 wt % of a dispersant based on dry weight;

[0019] (6) 0 to 2 wt. % of a lubricant, calculated on a dry weight basis.

[0020] Furthermore, the present invention provides a pharmaceutical tablet composition of perampanel tablets, comprising the following components:

[0021] (1) 2-4% by weight of perampanel based on dry weight;

[0022] (2) 70 to 85% by weight of lactose, calculated on a dry weight basis;

[0023] (3) 10 to 20 weight percent, based on dry weight, of low-substituted hydroxypropyl cellulose;

[0024] (4) 0 to 8% by weight of povidone, calculated on a dry weight basis;

[0025] (5) 0 to 0.3% by weight of medium chain triglycerides on a dry weight basis;

[0026] (6) 0 to 1.5% by weight of magnesium stearate, calculated on a dry weight basis.

[0027] Furthermore, the present invention provides a pharmaceutical tablet composition of perampanel tablets, comprising the following components:

[0028] (1) 2-4% by weight of perampanel based on dry weight;

[0029] (2) 70 to 85% by weight of lactose, calculated on a dry weight basis;

[0030] (3) 10 to 20 weight percent, based on dry weight, of low-substituted hydroxypropyl cellulose;

[0031] (4) 0 to 8% by weight of povidone, calculated on a dry weight basis;

[0032] (5) 0 to 0.3 wt % glycerol, calculated on a dry weight basis;

[0033] (6) 0 to 1.5% by weight of magnesium stearate, calculated on a dry weight basis.

[0034] The present invention provides a method for preparing a pharmaceutical composition containing perampanel, comprising the following steps:

[0035] (1) Dissolve povidone in purified water, stir until dissolved, add medium chain triglyceride or glycerol, homogenize for 5-10 minutes to make a white emulsion, add perampanel, stir evenly, and prepare a drug-containing adhesive solution;

[0036] (2) Use the wet granulation method to premix lactose and low-substituted hydroxypropyl cellulose excipient powder, then add the drug-containing adhesive, set the stirring speed and shear knife speed, and use atomization to spray granulation;

[0037] (3) drying the wet granules obtained in step (2) in a dryer;

[0038] (4) adding magnesium stearate to the granules prepared in step (3) and mixing the granules;

[0039] (5) tabletting the total mixed granules in step (4);

[0040] (6) Coating the tablets prepared in step (5).

[0041] Wherein, the amount of purified water in step (1) is 5 to 12 times the amount of the active ingredient of perampanel, preferably 7 to 10 times;

[0042] The homogenization process in step (1) is performed by using a high shear homogenizer at a speed of 4000 to 10000 rpm;

[0043] During the wet granulation process in step (2), the stirring speed is 120-180 rpm, the shearing knife speed is 600-1000 rpm, and the atomization pressure is 0.5-0.5 MPa;

[0044] In step (3), the inlet air temperature of the dryer is 60-80°C, and the inlet air volume is 20-30 Hz. After drying, take 1 gram of the particles and place them in a rapid moisture meter (105°C, 1.0g mode) to measure the moisture content. The moisture content of the particles is controlled to be 1.2%-3.5%;

[0045] During the total mixing process in step (4), the mixer speed is set to 7 rpm and the mixture is mixed for 5 minutes to obtain a total mixed powder;

[0046] In the tableting process in step (5), the hardness of the plain tablet is preferably controlled at 30-80N;

[0047] The coating material in step (6) is a film coating premix, the ingredients of which are hydroxypropyl methylcellulose, polyethylene glycol, talcum powder, calcium carbonate and red iron oxide.

[0048] The beneficial technical effects of the present invention are:

[0049] (1) The present invention can obtain a uniformly dispersed perampanel tablet pharmaceutical preparation by controlling the particle size of perampanel and adjusting the formulation.

[0050] (2) The present invention improves the tablet preparation method, controls the amount of water added during the wet granulation process and the moisture content of the granules after drying, and can ensure the stability of the production of a pharmaceutical composition with consistent crystal form, and the quality of the composition is stable. The problem of crystal form transformation caused by heat during the drying process after granulation during the preparation of the perampanel pharmaceutical composition is solved, and the quality of the drug is ensured to be stable. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 This is the dispersion diagram of the perampanel raw material in Prescription 1 in Example 2.

[0052] Figure 2 This is the dispersion diagram of the perampanel raw material in Prescription 2 in Example 2.

[0053] Figure 3 This is the dispersion diagram of the raw material of Perampanel in Prescription 3 in Example 2.

[0054] Figure 4This is the dispersion diagram of the raw material of Perampanel in Prescription 4 in Example 2.

[0055] Figure 5 This is the dispersion diagram of the raw material of Perampanel in Prescription 5 in Example 2.

[0056] Figure 6 This is the dispersion diagram of the raw material of Perampanel in Prescription 6 in Example 2.

[0057] Figure 7 This is the dispersion diagram of the raw material of Perampanel in Prescription 7 in Example 2. DETAILED DESCRIPTION

[0058] Specific embodiments of the present invention are described in detail below. It should be noted that the embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0059] The particle size of perampanel is preferably measured by a laser particle size analyzer. When the laser particle size distribution method is used to measure the particle size, the particle size and particle size distribution determination method (General Rules 0982 Method 3 Wet Method of the 2020 Edition of the Chinese Pharmacopoeia) (Malvern MS3000 or a laser particle size analyzer with equivalent performance) is followed to control the shading rate to 8% to 20% and measure the particle size data.

[0060] Example 1 Prescription Screening

[0061] Please screen the prescription according to Table 1.

[0062] Table 1 Prescription screening

[0063]

[0064] Preparation process:

[0065] 1. Crush the perampanel, add povidone to purified water, stir until dissolved, prepare an adhesive solution, then add medium chain triglycerides or hydroxypropyl cellulose SL or glycerol, homogenize for 5-10 minutes to prepare a white emulsion, add perampanel, and stir until evenly dispersed;

[0066] 2. Place lactose and low-substituted hydroxypropyl cellulose in a wet granulator, set the stirring speed to 120-180 rpm, the shear speed to 600-1000 rpm, and mix for 5 minutes to obtain a premixed powder;

[0067] 3. Add the drug-containing adhesive into the spray tank, set the atomization pressure to 0.2-0.5MPa, the stirring speed of the wet granulator to 120-180rpm, the shearing speed to 600-1000rpm, start the stirring speed and shearing speed of the wet granulator, and start the atomization liquid addition at the same time to wet granulate the premixed powder;

[0068] 4. Set the dryer inlet air temperature to 60~80℃ and the air volume to 20~30Hz to dry the wet particles. After drying, take 1 gram of particles and place them in a rapid moisture meter (105℃, 1.0g mode) to measure the moisture content.

[0069] 5. The dry granules are sieved with a 1.5 mm screen for dry granulation;

[0070] 6. After granulation, add magnesium stearate to the dry granules, set the mixer speed to 7 rpm, and mix for 5 minutes to obtain the total mixed powder;

[0071] 7. Place the total mixed powder in a high-speed tablet press for tableting, and control the hardness to 30~80N;

[0072] 8. Coating.

[0073] Example 2 Dispersion state test

[0074] (1) Examination of dispersion state under a microscope

[0075] The dispersion state of prescriptions 1 to 7 was observed using an electron microscope with a magnification of 20 times. Figure 1 to Figure 7 .

[0076] The results showed that: prescriptions 1 to 3 had serious aggregation, prescriptions 4 and 7 had no aggregation and were evenly dispersed in the composition; the aggregation of prescription 5 was significantly improved, but a small amount of raw material aggregates still existed; the aggregation of prescription 6 was improved, and a small amount of raw material aggregates still existed in the field of vision, but the aggregation was not obvious. This shows that by adjusting the raw material particle size and prescription, prescriptions 4 and 7 can better disperse the perampanel raw material in the pharmaceutical composition.

[0077] (2) Investigation of drug content uniformity

[0078] High performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0512) was used, with octadecylsilane bonded silica gel as filler; 0.1% ammonium acetate solution-acetonitrile (60:40) as mobile phase; flow rate of 1.0 ml per minute; column temperature of 35 °C; detection wavelength of 290 nm; injection volume of 20 μl. According to the requirements of the content uniformity inspection method of the Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0941, 10 tablets of each sample of prescription 1 to 7 were taken, and the relative content x of each single dose with a labeled amount of 1 0 0 was determined, and the mean X and standard deviation S and the absolute value A of the difference between the labeled amount and the mean (A=| 100 —X|) were calculated. If A+2.2S≤15.0, it meets the requirements. The smaller the value of A+2.2S, the better the content uniformity, and the larger the value, the worse the content uniformity. The results are shown in Table 2.

[0079] Table 2 Content uniformity test results

[0080]

[0081] The results show that: A+2.2S in prescription 1 does not meet the content uniformity limit requirements, indicating that the content in the preparation is uneven; the A+2.2S values ​​in prescriptions 2 to 7 all meet the content uniformity limit requirements, indicating that the content in the preparation is uniform. However, the results show that among the A+2.2S values ​​of prescriptions 2 to 7, prescription 4 has the smallest value, followed by prescription 7, followed by prescription 5 < prescription 6 < prescription 3 < prescription 2, indicating that the raw material particle size D 90 In the range of 120~150μm, it is not easy to mix evenly. By adjusting the raw material particle size and prescription, prescriptions 4~7 can make the preparation content uniform. Among them, prescriptions 4 and 7 have better dispersion effects, and prescription 4 has the best dispersion effect.

[0082] Example 3 Prescription Screening

[0083] Continue with prescription screening according to Table 3.

[0084] Table 3 Prescription screening

[0085]

[0086] Preparation process of prescriptions 8 to 11:

[0087] 1. Grind Perampanel into particles of size D 90 =40~90μm, add povidone to purified water, stir until dissolved, prepare adhesive solution, then add medium chain triglyceride, homogenize for 5-10 minutes to prepare white emulsion, add perampanel, stir until evenly dispersed;

[0088] 2. Place lactose and low-substituted hydroxypropyl cellulose in a wet granulator, set the stirring speed to 120-180 rpm, the shear speed to 600-1000 rpm, and mix for 5 minutes to obtain a premixed powder;

[0089] 3. Add the drug-containing adhesive into the spray tank, set the atomization pressure to 0.2-0.5MPa, the stirring speed of the wet granulator to 120-180rpm, the shearing speed to 600-1000rpm, start the stirring speed and shearing speed of the wet granulator, and start the atomization liquid addition at the same time to wet granulate the premixed powder;

[0090] 4. Set the dryer inlet air temperature to 60~80℃ and the air volume to 20~30Hz to dry the wet particles. After drying, take 1 gram of particles and place them in a rapid moisture meter (105℃, 1.0g mode) to measure the moisture content.

[0091] 5. The dry granules are sieved with a 1.5 mm screen for dry granulation;

[0092] 6. After granulation, add magnesium stearate to the dry granules, set the mixer speed to 7 rpm, and mix for 5 minutes to obtain the total mixed powder;

[0093] 7. Place the total mixed powder in a high-speed tablet press for tableting, and control the hardness to 30~80N;

[0094] 8. Coating.

[0095] Preparation process of prescription 12:

[0096] 1. Grind Perampanel into particles of size D 90 =40~90μm, add povidone to purified water, stir until dissolved, prepare adhesive solution, then add medium chain triglyceride, homogenize for 5-10 minutes to prepare white emulsion, add perampanel, stir until evenly dispersed;

[0097] 2. Place lactose and low-substituted hydroxypropyl cellulose in a wet granulator, set the stirring speed to 120-180 rpm, the shear speed to 600-1000 rpm, and mix for 5 minutes to obtain a premixed powder;

[0098] 3. Add the drug-containing adhesive into the spray tank, set the atomization pressure to 0.2-0.5MPa, the stirring speed of the wet granulator to 120-180rpm, the shearing speed to 600-1000rpm, start the stirring speed and shearing speed of the wet granulator, and start the atomization liquid addition at the same time to wet granulate the premixed powder;

[0099] 4. Set the dryer air inlet temperature to 60~80℃ and air volume to 20~30Hz, dry the wet particles, stop drying when the drying time reaches 1 / 2, take 1 gram of particles, and place them in a rapid moisture analyzer (105℃, 1.0g mode) to measure the moisture content;

[0100] 5. The dry granules are sieved with a 1.5 mm screen for dry granulation;

[0101] 6. After granulation, add magnesium stearate to the dry granules, set the mixer speed to 7 rpm, and mix for 5 minutes to obtain the total mixed powder;

[0102] 7. Place the total mixed powder in a high-speed tablet press for tableting, and control the hardness to 30~80N;

[0103] 8. Coating.

[0104] Example 4 Stability Test

[0105] (1) Determination of moisture content

[0106] The granules prepared in recipes 4, 8-12 were placed in a rapid moisture analyzer (105°C, 1.0g mode) to measure the moisture content. The results are as follows:

[0107] Table 4 Particle moisture measurement results

[0108]

[0109] (2) Tablet compression process inspection

[0110] The mixed powder prepared by prescriptions 4, 8-12 was tableted on a high-speed tablet press, and 5-10 tablets of the pressed plain tablets were taken using a tablet hardness tester to test the hardness, and the properties and hardness values ​​of the plain tablets were collected. The test results are shown in Table 5.

[0111] Table 5 Hardness test

[0112]

[0113] The results showed that the granules prepared by prescriptions 4, 8, 10-12 all had good fluidity and met the requirements for tableting. During the tableting process of the granules prepared by prescription 9, sticking occurred and they could not be pressed smoothly, indicating that the amount of water added during the wet granulation process should not be too much. Too much water can easily cause the moisture content of the granules to be too high after drying, affecting the smoothness of tableting.

[0114] (3) Crystal form investigation

[0115] The crystal form of the tablets prepared by prescriptions 4, 8, 10-12 was determined by X-ray diffraction method, and the results are as follows:

[0116] Table 6 Crystal form investigation

[0117]

[0118] The results showed that the pharmaceutical compositions prepared by prescriptions 4, 9-11 were all 3 / 4 hydrates, which were similar to the marketed perampanel tablets (trade name: Fycompa ® ) The crystal form of the pharmaceutical composition prepared by prescriptions 8 and 12 changed. Prescription 8 shows that the moisture content of the granules is lower than the control value (1.2%~3.5%), and the crystal form is prone to transformation. Prescription 12 shows that even if the moisture content of the granules is controlled within the control value range (1.2%~3.5%) by controlling the drying time, the crystal form of the obtained pharmaceutical composition still changes, indicating that the amount of water added during the granulation process needs to be strictly controlled. If too little water is added, the wet granulation process is uneven, and the granules that are not wetted are prone to lose crystal water during the drying process and become anhydrous crystal forms.

[0119] (4) Crystalline form investigation during stability process

[0120] Prescriptions 4, 10, and 11 were placed in an accelerated test (40°C / 75%RH) for 6 months and a long-term test (30°C / 65%RH) for 12 months. The crystal form was determined by X-ray diffraction. The results are as follows:

[0121] Table 7 Crystalline form observation during stability placement

[0122]

[0123] The results showed that the drug compositions prepared by prescriptions 4, 10, and 11 were all 3 / 4 hydrates. The crystal form did not change during the accelerated test (40°C / 75%RH) for 6 months and the long-term test (30°C / 65%RH) for 12 months, and they were all 3 / 4 hydrates.

Claims

1. A pharmaceutical composition containing perampanel, characterized in that: Contains the following ingredients: (1) 2-4% by weight of perampanel based on dry weight; (2) 70 to 85% by weight of lactose, calculated on a dry weight basis; (3) 10 to 20% by weight of low-substituted hydroxypropyl cellulose based on dry weight; (4) 0 to 8% by weight of povidone, calculated on a dry weight basis; (5) 0.04 to 0.1 wt % of a dispersant on a dry basis; (6) 0 to 1.5% by weight of magnesium stearate, calculated on a dry weight basis; The dispersant is a medium chain triglyceride or glycerol; the D 90 Particle size is 40-90 μm; The preparation method of the pharmaceutical composition containing perampanel comprises the following steps: (1) dissolving povidone in purified water, stirring until dissolved, adding medium chain triglyceride or glycerol, homogenizing for 5-10 minutes to prepare a white emulsion, adding perampanel, stirring evenly, and preparing a drug-containing adhesive solution; (2) premixing lactose and low-substituted hydroxypropyl cellulose excipient powder by wet granulation method, then adding drug-containing adhesive, setting stirring speed and shearing knife speed, and spraying granulation by atomization; (3) drying the wet granules in step (2) in a dryer; (4) adding magnesium stearate to the granules prepared in step (3) and mixing them; (5) tabletting the total mixed granules in step (4); (6) coating the tablets in step (5); The amount of purified water added in step (1) is 5 to 12 times the amount of the active ingredient of perampanel; After drying in step (3), the moisture content of the particles is 1.2% to 3.5%.

2. The method for preparing the pharmaceutical composition containing perampanel according to claim 1, characterized in that: The homogenization process in step (1) is performed by using a high shear homogenizer with a rotation speed of 4000 to 10000 rpm; in the wet granulation process in step (2), the stirring speed is 120 to 180 rpm, the shear knife speed is 600 to 1000 rpm, and the atomization pressure is 0.5 to 0.5 MPa.

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