Riluzole sustained-release tablet and preparation method thereof

Abstract

The application belongs to the technical field of medicine, and provides a riluzole sustained-release tablet and a preparation method thereof. The sustained-release tablet is composed of a tablet core containing riluzole, a filler, a disintegrant, a glidant, a lubricant and a sustained-release skeleton material, and a sustained-release coating layer containing Eudragit RL 30D, Eudragit RS 30D, triethyl citrate, dimethyl silicone oil emulsion and talc. The prepared riluzole sustained-release tablet is a sustained-release preparation combined with a skeleton type and a membrane-controlled type, has slow drug release, avoids the peak-valley phenomenon, has a simple preparation process, low technical difficulty, small batch difference, good release curve reproducibility and is suitable for large-scale production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine, and provides a riluzole sustained-release tablet and a preparation method thereof. BACKGROUND

[0002] The riluzole tablet is developed by Sanofi-Aventis Company, and is approved for marketing by FDA in 1996, and the specification is 50mg. Riluzole, that is, 2-amino-6-trifluoromethoxy benzothiazole, is suitable for prolonging the life of amyotrophic lateral sclerosis (ALS) patients or prolonging the time of developing to the time of needing mechanical ventilation support. The mechanism of action of riluzole is not clear, and the action can be related to inhibiting glutamate release, stabilizing the inactivation state of voltage-dependent sodium channels, and interfering with intracellular events after the combination of neurotransmitters and excitatory amino acid receptors.

[0003] Riluzole is almost insoluble in water, and is easily soluble in methanol or ethanol. It needs to be taken twice a day (50mg every 12 hours), and is taken orally at a fixed time every day, and the blood drug concentration fluctuates greatly, the peak concentration is high, and the adverse reactions are serious.

[0004] The sustained-release preparation refers to a preparation that slowly and non-constantly releases drugs in a specified medium according to requirements, and compared with the corresponding ordinary preparation, the drug frequency is reduced by half or is reduced, and the patient compliance can be significantly increased. The characteristic is that the active drug is released slowly, and after being absorbed into the blood, a long time of effective therapeutic blood drug concentration can be maintained.

[0005] An application patent with the application number 201910043880.3 and the invention name of a riluzole sustained-release oral suspension discloses a riluzole sustained-release oral suspension, and solves the drug compliance problem of the elderly children and other dysphagia groups. SUMMARY

[0006] The purpose of the application is to provide a riluzole sustained-release tablet and a preparation method thereof. The sustained-release tablet of the application is a sustained-release preparation combined with a matrix type and a membrane-controlled type, the drug is released slowly, the blood drug concentration is stable, the peak-trough phenomenon is avoided, and the effective blood drug concentration can be maintained for a long time, so that the best therapeutic effect can be achieved. Since the peak-trough phenomenon is reduced, the toxic and side effects of the drug are reduced, and the occurrence of drug resistance is reduced.

[0007] The specific technical scheme of the application is as follows:

[0008] The riluzole sustained-release tablet disclosed by the application is mainly composed of 85% to 95% of a drug-containing tablet core and 5% to 15% of a sustained-release coating layer. The drug-containing tablet core is mainly composed of riluzole, a filler, a disintegrant, a glidant, a lubricant and a sustained-release matrix material; and the sustained-release coating layer is mainly composed of Eudragit RL 30D, Eudragit RS 30D, triethyl citrate, dimethyl silicone oil and talc.

[0009] Preferably, the above-mentioned riluzole sustained-release tablet is composed of 90% drug-containing tablet core and 10% sustained-release coating layer.

[0010] Further preferably, the above-mentioned drug-containing tablet core is composed of the following components:

[0011]

[0012] More preferably, the above-mentioned drug-containing tablet core is composed of the following components:

[0013]

[0014] Further preferably, the above-mentioned sustained-release coating layer is composed of the following components:

[0015] Eudragit RL 30D 2%~7%

[0016] Eudragit RS 30D 24%~30%

[0017] Triethyl citrate 15%~20%

[0018] Dimethicone emulsion 0.1%~0.3%

[0019] Talc 3%~5%

[0020] Purified water 45%~50%.

[0021] More preferably, the above-mentioned sustained-release coating layer is composed of the following components:

[0022] Eudragit RL 30D 3%

[0023] Eudragit RS 30D 27%

[0024] Triethyl citrate 17%

[0025] Dimethicone emulsion 0.2%

[0026] Talc 4.5%

[0027] Purified water 48.3%

[0028] The above-mentioned sustained-release matrix material is one or more of hydroxyethyl cellulose, hypromellose, carbomer resin, sodium carboxymethyl cellulose, and sodium alginate; preferably, the above-mentioned sustained-release matrix material is hydroxyethyl cellulose.

[0029] The above-mentioned filler is a mixture of one or more of microcrystalline cellulose, lactose, starch, anhydrous calcium hydrogen phosphate, pregelatinized starch, and mannitol.

[0030] Preferably, the filler is microcrystalline cellulose, lactose;

[0031] Further preferably, the ratio of microcrystalline cellulose and lactose is 16:5-15;

[0032] More preferably, the ratio of microcrystalline cellulose and lactose is 16:9.

[0033] The above disintegrating agent is one or a mixture of more of low-substituted hydroxypropyl cellulose, dry starch, sodium carboxymethyl starch, cross-linked PVP.

[0034] Preferably, the disintegrating agent is low-substituted hydroxypropyl cellulose.

[0035] Preferably, the above flow agent is one or a mixture of more of microfine silica, silicon dioxide.

[0036] Preferably, the above lubricant is one or a mixture of more of magnesium stearate, microfine silica, hydrogenated vegetable oil, sodium stearyl fumarate.

[0037] Further preferably, the lubricant is magnesium stearate.

[0038] The present application also aims to provide a preparation method of the above riluzole sustained-release tablets, which mainly comprises the following steps:

[0039] A: Take the prescribed amount of riluzole, filler, disintegrating agent, sustained-release matrix material, and flow agent, mix, press into tablets, and obtain the tablets for standby;

[0040] B: Take the prescribed amount of sustained-release coating layer ingredients, prepare the coating liquid, and standby;

[0041] C: Coat the tablets obtained in step A with the coating liquid obtained in step B, and obtain the riluzole sustained-release tablets.

[0042] Preferably, the preparation method comprises the following steps:

[0043] A: Take the prescribed amount of riluzole and mix with microcrystalline cellulose and lactose, add the prescribed amount of low-substituted hydroxypropyl cellulose, hydroxyethyl cellulose, and microfine silica, mix, add the prescribed amount of magnesium stearate, mix, press into tablets, and obtain the tablets for standby;

[0044] B: Take the prescribed amount of sustained-release coating layer ingredients, prepare the coating liquid, and standby;

[0045] C: Coat the tablets obtained in step A with the coating liquid obtained in step B, and obtain the riluzole sustained-release tablets.

[0046] Compared with the prior art, the present application has the following technical effects:

[0047] The prepared riluzole sustained-release tablet is a sustained-release preparation combined with a matrix type and a membrane control type. The riluzole sustained-release tablet is slowly released in a digestive juice, has a relatively constant gastrointestinal transit time, avoids a dose burst phenomenon, and ensures the safety of clinical medication. Meanwhile, the riluzole sustained-release tablet has a large gastrointestinal distribution area, high drug bioavailability, a simple preparation process, low technical difficulty, small batch differences, good release curve reproducibility, and is conducive to large-scale industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0048] Figure 1 Cumulative release curves of riluzole sustained-release tablets obtained in Examples 1, 2, 3, 4, 5, 6, 7 and Comparative Examples 1, 2 DETAILED DESCRIPTION

[0049] Example 1

[0050] Drug-containing tablet core:

[0051] Riluzole 320g

[0052] Microcrystalline cellulose 256g

[0053] Lactose 144g

[0054] Low-substituted hydroxypropyl cellulose 24g

[0055] Silicon dioxide 8g

[0056] Magnesium stearate 8g

[0057] Hydroxyethyl cellulose 240g

[0058] Sustained-release coating layer:

[0059] Eudragit RL 30D 30g

[0060] Eudragit RS 30D 270g

[0061] Triethyl citrate 170g

[0062] Dimethyl silicone oil emulsion 2g

[0063] Talc 45g

[0064] Purified water 483g

[0065] Mix the riluzole, microcrystalline cellulose and lactose in a prescribed amount, and then mix the low-substituted hydroxypropyl cellulose, hydroxyethyl cellulose and microcrystalline silicon in a prescribed amount, and finally mix the magnesium stearate in a prescribed amount, and then press the mixture to obtain a tablet, which is ready for use.

[0066] Take the prescription amount of Eudragit RL 30D, Eudragit RS 30D, talc, triethyl citrate into water, homogenate, filter, add the prescription amount of dimethyl silicone oil defoaming, get the coating liquid, ready for use.

[0067] Coat the above obtained tablets in the coating pan with the above obtained coating liquid (coating weight gain is 10%), and riluzole sustained-release tablets are obtained.

[0068] Example 2

[0069] Drug-containing tablet core:

[0070] Riluzole 320g

[0071] Microcrystalline cellulose 305g

[0072] Lactose 95g

[0073] Low-substituted hydroxypropyl cellulose 24g

[0074] Silicon dioxide 8g

[0075] Magnesium stearate 8g

[0076] Hydroxyethyl cellulose 240g;

[0077] Sustained-release coating layer:

[0078] Eudragit RL 30D 30g

[0079] Eudragit RS 30D 270g

[0080] Triethyl citrate 170g

[0081] Dimethyl silicone oil emulsion 2g

[0082] Talc 45g

[0083] Purified water 483g;

[0084] The preparation method is referred to Example 1, wherein the coating weight gain is 10%.

[0085] Example 3

[0086] Drug-containing tablet core:

[0087] Riluzole 320g

[0088] Microcrystalline cellulose 206g

[0089] Lactose 194g

[0090] Low-substituted hydroxypropyl cellulose 24g

[0091] Silica 8g

[0092] Magnesium stearate 8g

[0093] Hydroxyethyl cellulose 240g;

[0094] Sustained release coating layer:

[0095] Eudragit RL 30D 30g

[0096] Eudragit RS 30D 270g

[0097] Triethyl citrate 170g

[0098] Dimethicone emulsion 2g

[0099] Talc 45g

[0100] Purified water 483g;

[0101] Preparation method according to Example 1 with a coating weight gain of 10%.

[0102] Example 4

[0103] Drug-containing tablet core:

[0104] Riluzole 200g

[0105] Starch 350g

[0106] Cross-linked PVP 50g

[0107] Colloidal silica 5g

[0108] Hydrogenated vegetable oil 10g

[0109] Hydroxypropyl methyl cellulose 385g;

[0110] Sustained release coating layer:

[0111] Eudragit RL 30D 70g

[0112] Eudragit RS 30D 240g

[0113] Triethyl citrate 150g

[0114] Dimethicone emulsion 3g

[0115] Talc 50g

[0116] Purified water 487;

[0117] Preparation method according to Example 1 with a coating weight gain of 5%.

[0118] Example 5

[0119] Drug-containing core:

[0120] Riluzole 400 g

[0121] Mannitol 415 g

[0122] Dried starch 20 g

[0123] Silica 10 g

[0124] Sodium stearyl fumarate 5 g

[0125] Carbomer resin 150 g;

[0126] Sustained-release coating layer:

[0127] Eudragit RL 30D 20 g

[0128] Eudragit RS 30D 300 g

[0129] Triethyl citrate 198 g

[0130] Dimethicone emulsion 2 g

[0131] Talc 30 g

[0132] Purified water 450 g;

[0133] Reference Example 1 for the preparation method, wherein the coating weight gain is 10%.

[0134] Example 6

[0135] Drug-containing core:

[0136] Riluzole 214 g

[0137] Pre-gelatinized starch 350 g

[0138] Sodium carboxymethyl starch 20 g

[0139] Silica 8 g

[0140] Silica 8 g

[0141] Sodium carboxymethyl cellulose 400 g;

[0142] Sustained-release coating layer:

[0143] Eudragit RL 30D 53 g

[0144] Eudragit RS 30D 200 g

[0145] Triethyl citrate 200 g

[0146] 2g of dimethyl silicone oil emulsion

[0147] 45g of talcum powder

[0148] 500g of purified water;

[0149] The preparation method is the same as in Example 1, wherein the coating weight gain is 15%.

[0150] Example 7

[0151] Tablet core containing medication:

[0152] Riluzole 310.00g

[0153] Anhydrous dicalcium phosphate 500.00g

[0154] Low-substituted hydroxypropyl cellulose 24.00g

[0155] 8.00g of silicon dioxide

[0156] Magnesium stearate 8.00g

[0157] Sodium alginate 150.00g;

[0158] Sustained-release coating layer:

[0159] Eudragit RL 30D 30g

[0160] Eudragit RS 30D 270g

[0161] 170g of triethyl citrate

[0162] 2g of dimethyl silicone oil emulsion

[0163] 45g of talcum powder

[0164] 483g of purified water;

[0165] The preparation method is the same as in Example 1, wherein the coating weight gain is 10%.

[0166] Comparative Example 1

[0167] Riluzole 320g

[0168] 256g of microcrystalline cellulose

[0169] 144g of lactose

[0170] Low-substituted hydroxypropyl cellulose 24g

[0171] 8g of silicon dioxide

[0172] 8g magnesium stearate

[0173] Hydroxyethyl cellulose 240 g;

[0174] Mix the riluzole, microcrystalline cellulose and lactose in the prescription amount, then add the low-substituted hydroxypropyl cellulose and hydroxyethyl cellulose in the prescription amount, mix well, and finally add the magnesium stearate in the prescription amount, mix well, and press into tablets to obtain the riluzole sustained-release tablets.

[0175] Comparative Example 2

[0176] Riluzole 320 g

[0177] Microcrystalline cellulose 256 g

[0178] Lactose 144 g

[0179] Low-substituted hydroxypropyl cellulose 24 g

[0180] Silicon dioxide 8 g

[0181] Magnesium stearate 8 g;

[0182] Sustained-release coating layer:

[0183] Eudragit RL 30D 30 g

[0184] Eudragit RS 30D 270 g

[0185] Triethyl citrate 170 g

[0186] Dimethyl silicone oil emulsion 2 g

[0187] Talc 45 g

[0188] Purified water 483 g;

[0189] Mix the riluzole, microcrystalline cellulose and lactose in the prescription amount, then add the low-substituted hydroxypropyl cellulose and microcrystalline silicon in the prescription amount, mix well, and finally add the magnesium stearate in the prescription amount, mix well, and press into tablets to obtain the riluzole sustained-release tablets.

[0190] Add the Eudragit RL 30D, Eudragit RS 30D, talc and triethyl citrate in the prescription amount to water, homogenize in a homogenizer, filter, and add the dimethyl silicone oil in the prescription amount to defoam to obtain the coating liquid, which is ready for use.

[0191] Coat the above-obtained tablets in a coating pan with the above-obtained coating liquid (coating weight gain is 10%), and obtain the riluzole sustained-release tablets.

[0192] Release degree detection

[0193] The release degree is determined by the dissolution and release determination method (Chinese Pharmacopoeia 2015 Edition Part IV General Rules 0931 Second Method).

[0194] The riluzole sustained-release tablets obtained in Examples 1-7 and Comparative Examples 1-2 are respectively taken as the dissolution medium of 900ml of 0.1mol / L hydrochloric acid solution, the rotation speed is 50 revolutions per minute, the operation is performed according to the method, and 10ml of sample is taken at 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours and 12 hours. The sample is filtered, and 10ml of dissolution medium at the same temperature is immediately supplemented in the operation container. 5ml of the filtrate is precisely measured, placed in a 100ml volumetric flask, diluted to the calibration mark with 0.1mol / L hydrochloric acid solution, and used as the test sample solution. An appropriate amount of riluzole reference substance is precisely weighed, dissolved and quantitatively diluted with 0.1mol / L hydrochloric acid solution to prepare a solution containing about 10ug per 1ml, which is used as the reference substance solution. The test sample solution and the reference substance solution are respectively taken, the absorbance is determined at a wavelength of 254nm by ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2015 Edition Part IV General Rules 0401), and the release amount of each tablet at different times is calculated. The test results are shown in Table 1.

[0195] According to the experimental results, the riluzole sustained-release tablets prepared by the present application are steadily released within 14h, which can effectively avoid the burst release phenomenon.

[0196] Table 1: In-vitro cumulative release degree of riluzole sustained-release tablets (%)

[0197] Time (h) 1 2 4 6 8 10 12 14 Example 1 26 34 43 52 64 74 87 96 Example 2 29 36 46 60 69 81 88 96 Example 3 23 29 39 48 62 71 85 93 Example 4 35 47 55 65 80 86 92 97 Example 5 33 50 59 67 80 86 90 95 Example 6 36 45 53 65 76 85 91 98 Example 7 39 48 56 66 78 83 90 95 Comparative Example 1 56 72 86 95 95 95 95 95 Comparative Example 2 49 60 72 83 94 94 94 94

Claims

1. A riluzole sustained-release tablet, characterized in that, The riluzole sustained-release tablets are mainly composed of 85%~95% drug-containing tablet core and 5%~15% sustained-release coating layer; the drug-containing tablet core is mainly composed of riluzole, filler, disintegrant, glidant, lubricant, and sustained-release matrix material, wherein the sustained-release matrix material is hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carbomer resin, sodium carboxymethyl cellulose, or sodium alginate; the sustained-release coating layer is mainly composed of Eudragit RL 30D, Eudragit RS 30D, triethyl citrate, dimethyl silicone oil, and talc.

2. The riluzole sustained-release tablet according to claim 1, characterized in that, The riluzole sustained-release tablets consist of a 90% tablet core and a 10% sustained-release coating layer.

3. The riluzole sustained-release tablet according to claim 1, characterized in that, The medicated tablet core is composed of the following components: Riluzole 20%~40% Filler 35%~50% Disintegrant 2%~5% Flow aid 0.5%~1% Lubricant 0.5%~1% Sustained-release matrix material: 15%~40%.

4. The riluzole sustained-release tablet according to claim 1, characterized in that, The sustained-release coating layer is composed of the following components: Eudragit RL 30D 2%~7% Eudragit RS 30D 24%~30% Triethyl citrate 15%~20% Dimethyl silicone oil emulsion 0.1%~0.3% Talc powder 3%~5% Purified water 45%~50%.

5. The riluzole sustained-release tablet according to claim 1, characterized in that, The filler is one or more of the following: microcrystalline cellulose, lactose, starch, anhydrous dicalcium phosphate, pregelatinized starch, and mannitol.

6. The riluzole sustained-release tablet according to claim 1, characterized in that, The filler is microcrystalline cellulose and lactose, and the ratio of microcrystalline cellulose to lactose is 16:5-15.

7. The riluzole sustained-release tablet according to claim 1, characterized in that... The disintegrant is one or more of the following: low-substituted hydroxypropyl cellulose, dry starch, sodium carboxymethyl starch, and cross-linked PVP.

8. The riluzole sustained-release tablet according to claim 1, characterized in that... The flow aid is one or a mixture of two of micronized silica gel and silicon dioxide.

9. The riluzole sustained-release tablet according to claim 1, characterized in that... The lubricant is one or a mixture of magnesium stearate, micronized silica gel, hydrogenated vegetable oil, and sodium stearate fumarate.

10. The method for preparing riluzole sustained-release tablets according to claim 1, characterized in that, The preparation method includes the following steps: A: Take the prescribed amount of riluzole, filler, disintegrant, sustained-release matrix material, and glidant, mix them, compress them into tablets, and prepare unprocessed tablets for later use; B: Take the prescribed amount of sustained-release coating ingredients, prepare the coating solution, and set aside. C: Coat the tablets obtained in step A with the coating solution obtained in step B to obtain riluzole sustained-release tablets.

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