Dimethyl fumarate enteric-coated tablets and enteric-coated capsules

Abstract

The present invention provides a dimethyl fumarate enteric-coated tablet, which includes a dimethyl fumarate tablet, an isolation layer and an enteric layer from the inside to the outside, and the coating material for the isolation layer is a mixture of hydroxypropyl cellulose, methacrylic acid-methyl methacrylate copolymer 1:1, talcum powder, and triethyl citrate in a mass ratio of 5-8:2-4:0.5-1.5:0.5-1.5, wherein the weight-average molecular weight of hydroxypropyl cellulose is less than 100000Da. The present invention also provides a dimethyl fumarate enteric-coated capsule. The present invention adopts a specific isolation layer coating material, which can realize the coating process at low temperature, thereby effectively inhibiting the sublimation of dimethyl fumarate, reducing raw material loss, and improving the safety and controllability of the production process. The dimethyl fumarate enteric-coated tablets and enteric-coated capsules provided by the present invention have simple prescriptions and compositions, do not require expensive auxiliary materials and reagents, have a simple preparation process, and are suitable for industrial-scale production.

Description

Technical Field

[0001] The invention relates to the field of medicine, in particular to a dimethyl fumarate enteric-coated tablet and a dimethyl fumarate enteric-coated capsule. Background Art

[0002] Dimethyl fumarate, English name is Dimethyl Fumarate, chemical name is (E)-2-butenedioic acid dimethyl ester, CAS number: 624-49-7, molecular formula is C 6 H 8 O 4 , molecular weight is 144.13, chemical structure is as follows:

[0003]

[0004] The raw material of dimethyl fumarate is powder crystal, with a melting point of 103-104℃, a boiling point of 193℃, a relative density of 1.37, soluble in ethyl acetate, chloroform, acetone and alcohols, slightly soluble in ether, insoluble in water, and has the characteristics of high efficiency, low toxicity, broad-spectrum antibacterial, easy sublimation, and obvious allergic reaction after direct contact with the human body. It was first approved in Germany in 1994 for the treatment of psoriasis. According to its evidence-based medicine guideline report for the treatment of psoriasis, dimethyl fumarate has good long-term safety. In March 2013, the FDA approved dimethyl fumarate for the treatment of relapsing MS patients, including clinically isolated syndrome, relapsing disease and active secondary progressive disease. In January 2014, dimethyl fumarate was approved for marketing by the European EMA, with specifications of 120mg and 240mg, and the dosage form is sustained-release capsules.

[0005] The mechanism of action of dimethyl fumarate in treating MS may be that it has nuclear transcription factor-κB (NF-κB) activation inhibitor activity, which can activate the antioxidant Nrf2-ARE channel in the human body to prevent nerve cell damage and inflammation, resist the damage of reactive oxygen to cells, and thus reduce the oxidative stress response of demyelination. Dimethyl fumarate is rapidly hydrolyzed by enzymes and converted into monomethyl fumarate (MMF) before circulation in the human body. The main metabolites of dimethyl fumarate are fumaric acid, citric acid, and MMF, and the main elimination pathway is carbon dioxide. The terminal T1 / 2 of MMF is about 1h, and the general elimination period is 24h. After giving more doses of dimethyl fumarate, MMF was not observed to accumulate in the body.

[0006] The main absorption site of dimethyl fumarate is the intestine, but the compound has strong gastrointestinal reactions. The most common adverse reactions are diarrhea, stomach pain and flatulence, which seriously affect the adaptability of patients. Some patients even interrupt treatment because they cannot tolerate it. Therefore, the clinical dosage form of dimethyl fumarate is designed as a multi-particle drug delivery system, which can reduce the impact of food on its release and absorption, make the drug-time curve more stable, and have better reproducibility. At the same time, it can reduce local irritation of the gastrointestinal tract, reduce adverse reactions and medication risks, and improve the stability of the drug. However, the raw material of dimethyl fumarate is easy to sublimate and is allergenic to the human body. Therefore, the existing preparation process often uses an isolation system and over-feeding to ensure the accuracy of the product content and the safety of personnel, which leads to high product production costs and difficult product quality control. Summary of the invention

[0007] In order to make up for the deficiencies in the prior art, an object of the present invention is to provide a dimethyl fumarate enteric-coated tablet, which can effectively overcome the shortcomings of dimethyl fumarate such as easy sublimation, large raw material consumption, poor process controllability and safety by adopting a specific isolation layer coating material for coating, thereby improving production efficiency and reducing production costs.

[0008] Another object of the present invention is to provide a dimethyl fumarate enteric-coated capsule.

[0009] The first aspect of the present invention provides a dimethyl fumarate enteric-coated tablet, which comprises, from the inside to the outside, a dimethyl fumarate tablet, an isolation layer and an enteric layer, wherein the coating material used for the isolation layer is a mixture of hydroxypropyl cellulose, methacrylic acid-methyl methacrylate copolymer 1:1, talcum powder, and triethyl citrate in a mass ratio of 5-8:2-4:0.5-1.5:0.5-1.5, wherein the weight average molecular weight of the hydroxypropyl cellulose is less than 100000Da.

[0010] The raw material of dimethyl fumarate is easy to sublimate and difficult to dissolve in water, and usually needs to be prepared as a multi-layer coated multi-particle drug release system. For the isolation layer coating process of dimethyl fumarate tablets, a higher temperature is generally required to dry the coating solvent and form a film. Especially in the initial stage, the raw material of dimethyl fumarate in the tablets is fully exposed to the hot air environment and is easy to sublimate quickly, resulting in serious loss of raw materials. In addition, the sublimated dimethyl fumarate is also easy to cause human allergies in operators, so it also has a higher safety risk.

[0011] In view of the characteristics of dimethyl fumarate that it is easy to sublimate during the coating process, thus causing human allergies, large raw material consumption, and poor process controllability, the inventors of the present invention adopt a mixture of ultra-low viscosity hydroxypropyl cellulose and methacrylic acid-methyl methacrylate copolymer (1:1) as an isolation layer film-forming material, which can form an isolation layer by performing the coating process at a low temperature, significantly reducing the loss of dimethyl fumarate raw materials, and eliminating the need for excessive input of raw materials. Therefore, the process and product quality are more controllable, the production efficiency is improved, and the production cost is reduced. Moreover, since the sublimation of dimethyl fumarate is effectively suppressed, the safety of the production process can also be improved, and the industrial applicability is better.

[0012] In some preferred embodiments, the coating material for the isolation layer may be a mixture of hydroxypropyl cellulose, methacrylic acid-methyl methacrylate copolymer 1:1, talcum powder, and triethyl citrate in a mass ratio of 5.5-6.5:2-3:0.8-1.2:0.8-1.2. In some more preferred embodiments, the coating material for the isolation layer may be a mixture of hydroxypropyl cellulose, methacrylic acid-methyl methacrylate copolymer 1:1, talcum powder, and triethyl citrate in a mass ratio of 6:2.5:1:1.

[0013] In some preferred embodiments, the weight average molecular weight of the hydroxypropyl cellulose is less than 90000 Da. In other preferred embodiments, the hydroxypropyl cellulose can be selected from one or both of hydroxypropyl cellulose EF and hydroxypropyl cellulose LF, or can be selected from other hydroxypropyl celluloses with equivalent average molecular weight distribution and film-forming properties.

[0014] In the dimethyl fumarate enteric-coated tablets provided by the present invention, the weight of the isolation layer may be 3-6% of the weight of the dimethyl fumarate tablets. In some preferred embodiments, the weight of the isolation layer may be 4-5% of the weight of the dimethyl fumarate tablets.

[0015] In the dimethyl fumarate enteric-coated tablets provided by the present invention, the isolation layer can be formed by the following process: using anhydrous ethanol to prepare a suspension with a concentration of 5 to 10 wt% (preferably 8 to 9 wt%) of the coating material for the isolation layer, and using the suspension to coat the dimethyl fumarate tablets, wherein the temperature during the coating process does not exceed 30° C. In some preferred embodiments, the temperature during the coating process does not exceed 25° C.

[0016] In the dimethyl fumarate enteric-coated tablets provided by the present invention, the dimethyl fumarate tablets can include 35-70% of dimethyl fumarate, 15-45% of diluent, 5-15% of disintegrant, 6-15% of glidant and 0.5-1.5% of lubricant by mass percentage. In some preferred embodiments, the dimethyl fumarate tablets can include 50-60% of dimethyl fumarate, 20-35% of diluent, 6-10% of disintegrant, 6-10% of glidant and 0.5-1% of lubricant by mass percentage. In some more preferred embodiments, the dimethyl fumarate tablets can include 50-55% of dimethyl fumarate, 25-32% of diluent, 8-10% of disintegrant, 8-10% of glidant and 0.8-1% of lubricant by mass percentage.

[0017] In the dimethyl fumarate enteric-coated tablets provided by the present invention, the diluent, disintegrant, glidant and lubricant can be any of the common types in the art.

[0018] In some preferred embodiments, the diluent may be selected from one or more of silicified microcrystalline cellulose, spray-dried lactose, microcrystalline cellulose, and mannitol. In some more preferred embodiments, the diluent may be selected from a mixture of silicified microcrystalline cellulose and microcrystalline cellulose KG1000 in a mass ratio of 4 to 6:1.

[0019] In some preferred embodiments, the disintegrant may be selected from one or more of cross-linked carboxymethyl cellulose sodium, sodium carboxymethyl starch, and cross-linked polyvinylpyrrolidone XL-10. In some more preferred embodiments, the disintegrant may be selected from cross-linked carboxymethyl cellulose sodium.

[0020] In some preferred embodiments, the glidant may be selected from one or more of silicon dioxide, talc, and sodium lauryl sulfate. In some more preferred embodiments, the glidant may be selected from a mixture of talc and silicon dioxide in a mass ratio of 1:1 to 1.5.

[0021] In some preferred embodiments, the lubricant can be selected from one or more of magnesium stearate, sodium stearyl fumarate, and sodium glycinate. In some more preferred embodiments, the lubricant can be selected from magnesium stearate.

[0022] In the dimethyl fumarate enteric-coated tablets provided by the present invention, the dimethyl fumarate tablets can be formed by the following process: crushing the dimethyl fumarate raw material to a particle size distribution d(90) <200 μm, and then mixing the crushed dimethyl fumarate raw material with the glidant, diluent, disintegrant and lubricant and tableting to obtain the tablets.

[0023] In some preferred embodiments, the dimethyl fumarate tablets are formed by the following process: crushing the dimethyl fumarate API to a particle size distribution of d(90) <200 μm, then mixing the crushed dimethyl fumarate API with the glidant to obtain a mixture 1, then mixing the mixture 1 with the diluent and disintegrant to obtain a mixture 2, then mixing the mixture 2 with the lubricant to obtain a mixture 3, and finally tableting the mixture 3. Mixing the crushed dimethyl fumarate API with the glidant, diluent, disintegrant, and lubricant in a specific order can achieve a better tableting effect.

[0024] In some more preferred embodiments, the dimethyl fumarate API is crushed using a hammer mill, and the API is stored at a temperature below 8° C. until its temperature is consistent with the ambient temperature before crushing. Crushing the API at low temperature is also beneficial to reduce the sublimation of dimethyl fumarate.

[0025] In some more preferred embodiments, the particle size of the dimethyl fumarate API after pulverization is 80 to 150 μm.

[0026] In some more preferred embodiments, the tablet hardness of the dimethyl fumarate tablet during tabletting is 20-40 kgf, the weight of a single tablet is 7-10 mg, and the diameter is 1.5-3 mm.

[0027] In the dimethyl fumarate enteric-coated tablets provided by the present invention, the coating material for the enteric layer can be a mixture of methacrylic acid-ethyl acrylate copolymer aqueous dispersion L30D-55, talcum powder, triethyl citrate, and polyethylene glycol 4000 in a mass ratio of 13 to 18: 1 to 3: 0.5 to 1.5: 0.05 to 0.15. In some preferred embodiments, the coating material for the enteric layer can be a mixture of methacrylic acid-ethyl acrylate copolymer aqueous dispersion L30D-55, talcum powder, triethyl citrate, and polyethylene glycol 4000 in a mass ratio of 13 to 18: 1 to 2: 0.8 to 1.2: 0.08 to 0.12. In some more preferred embodiments, the coating material for the enteric layer can be a mixture of methacrylic acid-ethyl acrylate copolymer aqueous dispersion L30D-55, talc, triethyl citrate, and polyethylene glycol 4000 in a mass ratio of 13-18:1.48-1.52:1:0.1.

[0028] In the dimethyl fumarate enteric-coated tablets provided by the present invention, the weight of the enteric layer can be 10-18% of the weight of the dimethyl fumarate tablets coated with the isolation layer. In some preferred embodiments, the weight of the enteric layer can be 13-17% of the weight of the dimethyl fumarate tablets coated with the isolation layer.

[0029] In the dimethyl fumarate enteric-coated tablets provided by the present invention, the enteric layer can be formed by the following process: using purified water to prepare a suspension with a concentration of 14 to 17 wt% of the coating material for the enteric layer, using the suspension to coat the dimethyl fumarate tablet coated with the isolation layer, and curing for 24 to 48 hours in a dry heat environment at 40 to 60° C. after coating. In some preferred embodiments, curing for 24 to 30 hours in a dry heat environment at 40 to 45° C. after coating.

[0030] The second aspect of the present invention provides a dimethyl fumarate enteric-coated capsule, comprising a capsule shell and a filler in the capsule shell, wherein the filler is the dimethyl fumarate enteric-coated tablet described in any one of the above technical solutions.

[0031] In some preferred embodiments, the dimethyl fumarate enteric-coated capsules provided by the present invention can be prepared by the following process:

[0032] 1) crushing the dimethyl fumarate raw material, sieving and setting aside;

[0033] 2) uniformly mixing the crushed dimethyl fumarate API with a prescribed amount of a flow aid to obtain a mixture 1;

[0034] 3) uniformly mixing the mixture 1 with the prescribed amount of diluent and disintegrant to obtain a mixture 2;

[0035] 4) uniformly mixing the mixture 2 with the prescribed amount of lubricant to obtain a mixture 3;

[0036] 5) determining the content of the active ingredient dimethyl fumarate in the mixture 3, calculating the tablet weight, and tableting to prepare dimethyl fumarate tablets;

[0037] 6) using an isolation layer coating material to coat the dimethyl fumarate tablets at low temperature, wherein the coating weight gain is controlled within a range of 3 to 6 wt %, to obtain a dimethyl fumarate isolation tablet;

[0038] 7) Enteric coating the dimethyl fumarate isolation tablet with an enteric coating material, wherein the coating weight gain is controlled within a range of 10 to 18 wt %, to obtain dimethyl fumarate enteric-coated tablets;

[0039] 8) curing the dimethyl fumarate enteric-coated tablets in a dry heat environment at a temperature of 40 to 60° C. for 24 to 48 hours (preferably curing in a dry heat environment at a temperature of 40 to 45° C. for 24 to 30 hours), and cooling to obtain a dimethyl fumarate enteric-coated capsule intermediate;

[0040] 9) placing the dimethyl fumarate enteric-coated capsule intermediate in a capsule filling machine, counting, filling and packaging according to product specifications to obtain dimethyl fumarate enteric-coated capsules.

[0041] The technical solution provided by the present invention has the following advantages:

[0042] 1) The present invention adopts a specific isolation layer coating material, which can realize the coating process at a low temperature, thereby effectively inhibiting the sublimation of dimethyl fumarate, reducing raw material loss, and improving the safety and controllability of the production process, thereby greatly improving production efficiency and reducing production costs.

[0043] 2) The dimethyl fumarate enteric-coated tablets and enteric-coated capsules provided by the present invention have simple formulations and compositions, do not require expensive auxiliary materials and reagents, have simple preparation processes, and are suitable for industrial-scale production.

[0044] 3) The dimethyl fumarate enteric-coated tablets and enteric-coated capsules provided by the present invention have high product quality, good appearance, shape, release and other properties, are conducive to expanding the clinical application of dimethyl fumarate preparations, and have important economic and social value. DETAILED DESCRIPTION

[0045] The technical solution of the present invention is further described in detail below in conjunction with specific embodiments.

[0046] Unless otherwise specified, the raw materials or reagents used in the examples of the present invention are commercially available products.

[0047] The percentages used in the embodiments of the present invention are all by mass unless otherwise specified.

[0048] The methods for determining the content of the plain tablets, the isolation tablets, and the enteric-coated capsules involved in the embodiments of the present invention all adopt the high performance liquid chromatography method in accordance with the general rules 0512 of Part IV of the 2020 edition of the Chinese Pharmacopoeia; the specific method for determining the content is as follows: (1) Test solution: Take about 2.4 g of the sample to be tested, accurately weigh it, and place it in a 250 ml volumetric flask, add about 200 ml of the extractant [phosphate buffer (0.01 mol of potassium dihydrogen phosphate in 1000 ml of water, adjust the pH value to 6.8 with saturated sodium hydroxide)-acetonitrile (40:60)], shake it ultrasonically for 10 minutes, dilute it to the scale with the extractant, shake it well, take an appropriate amount of solution, centrifuge it for 10 minutes (3000 rap / min), accurately measure 1 ml of the supernatant, place it in a 200 ml volumetric flask, add the mobile phase to dilute it to the scale, filter it, and take the filtrate as the test solution. (2) Reference solution: Take an appropriate amount of dimethyl fumarate reference substance, weigh it accurately, add the mobile phase to dissolve it and quantitatively dilute it to make a solution containing about 24μg per 1ml. (3) Chromatographic conditions: Use octadecylsilane bonded silica gel as filler; phosphoric acid water (1000ml water contains 1ml phosphoric acid)-acetonitrile (70:30) as mobile phase; detection wavelength is 210nm; injection volume is 10μl. (4) System suitability requirements: In the reference chromatogram, the theoretical plate number calculated based on the dimethyl fumarate peak is not less than 5000. (5) Determination method: Accurately measure the reference solution and the test solution, inject them into the liquid chromatograph respectively, and record the chromatogram. Calculate the dimethyl fumarate (in terms of C 6 H 8 O 4 Measured) content.

[0049] The release rate determination method involved in the embodiments of the present invention adopts the second method of 0931 of the fourth general rule of the 2020 edition of the Chinese Pharmacopoeia. The specific determination method is:

[0050] (1) Release in acid

[0051] Release conditions: 500ml of 0.1mol / l hydrochloric acid solution is used as the release medium, heated to 37℃±0.5℃, and the sample to be tested is placed in the solution, the speed is 100 rpm, and the release liquid is aspirated after 2 hours, filtered, and the filtrate is taken for determination. Reference solution: Take an appropriate amount of dimethyl fumarate reference substance, accurately weigh it, add the mobile phase to dissolve it to make a solution containing about 0.48mg (240mg specification) or 0.24mg (120mg specification) per 1ml, as the reference solution. Chromatographic conditions: Use octadecylsilane bonded silica gel as the filler (100mm×4.6mm, 5μm); use phosphate buffer (containing 0.02mol of potassium dihydrogen phosphate per 1000ml, and adjust the pH value to 2.5 with phosphoric acid)-acetonitrile (70:30) as the mobile phase; the detection wavelength is 250nm; the injection volume is 5μl. System suitability requirements: In the reference substance chromatogram, the theoretical plate number calculated based on the dimethyl fumarate peak is not less than 3000. Determination method: Accurately measure the reference substance solution and the test solution, inject them into the liquid chromatograph respectively, record the chromatogram, and calculate the release amount of each capsule. Limit: The release amount of each capsule is not more than 10% of the labeled amount.

[0052] (2) Release amount in buffer

[0053] Release conditions: discard the acid solution in each dissolution cup under the item of release in acid, and immediately add 500 ml of phosphate buffer (pH 6.8) preheated to 37℃±0.5℃ (take 6.80g of potassium dihydrogen phosphate, add 112.0ml of 0.2mol / l sodium hydroxide solution to dissolve, dilute to 1000ml with water, shake well, and obtain), the speed is 100 rpm, continue to release for 15 minutes, absorb the release liquid, filter, and take the filtrate. Reference solution: see under the item of release in acid. Chromatographic conditions and system suitability requirements: see under the item of release in acid. Determination method: accurately measure the reference solution and the test solution, inject them into the liquid chromatograph respectively, record the chromatogram, and calculate the release amount of each capsule. Limit: 80% of the labeled amount, which should meet the requirements.

[0054] Example 1-4 Preparation of dimethyl fumarate tablets

[0055] The prescription of dimethyl fumarate tablets is shown in Table 1.

[0056] Table 1 Prescription of dimethyl fumarate tablets (unit: mg)

[0057]

[0058] The preparation process of the dimethyl fumarate tablets of Examples 1-4 is as follows:

[0059] 1. Store the dimethyl fumarate API at a temperature below 8°C until its temperature is consistent with the ambient temperature, crush it with a hammer mill and pass it through a 60-mesh sieve (the particle size distribution d(90) is controlled to be less than 200 μm).

[0060] 2. Weigh the crushed dimethyl fumarate raw material, talcum powder and silicon dioxide in the prescribed amount and place them in a multi-directional motion mixer, set the speed to 10 rpm, and mix for 5 to 10 minutes to obtain a mixture 1.

[0061] 3. Add the prescribed amount of silicified microcrystalline cellulose, microcrystalline cellulose KG1000 and cross-linked sodium carboxymethyl cellulose to mixture 1, and continue mixing for 5 to 10 minutes to obtain mixture 2.

[0062] 4. Add magnesium stearate to mixture 2 and continue mixing for 3 minutes to obtain mixture 3.

[0063] 5. Determine the content of dimethyl fumarate, the active ingredient in mixture 3, and calculate the tablet weight. The dimethyl fumarate tablets were prepared by pressing the tablets with a shallow concave round mold of mm.

[0064] In the process of preparing dimethyl fumarate tablets in Example 1-4, monitoring parameters such as appearance, powder compressibility, powder fluidity (angle of repose), tablet hardness and friability were monitored. The process monitoring results are shown in Table 2.

[0065] Table 2 Monitoring and testing results of the preparation process of the plain tablets of Examples 1-4

[0066]

[0067]

[0068] The above results show that the intermediate materials of Examples 1-3 have good fluidity and good compressibility, while the material of Example 4 has slightly poor fluidity and can barely be tableted. The hardness, appearance and friability of the dimethyl fumarate tablets prepared from Examples 1-4 all meet the quality requirements.

[0069] Example 5-8 Preparation of dimethyl fumarate isolation sheet

[0070] The plain tablets prepared in Example 3 were coated with an isolation layer. The prescription of the isolation layer coating material is shown in Table 3.

[0071] Table 3 Separation layer coating material prescription (unit: mg)

[0072]

[0073] The preparation process of the dimethyl fumarate isolation sheet of Example 5-8 is as follows:

[0074] 1. Pour anhydrous ethanol into a stainless steel barrel, turn on the stirrer, add the prescribed amount of methacrylic acid-methyl methacrylate copolymer (1:1) and hydroxypropyl cellulose with different average molecular weight distributions (i.e., hydroxypropyl cellulose EF, LF, JF, GF), and continue stirring until completely dissolved to obtain solution 1.

[0075] 2. Slowly add the prescribed amount of triethyl citrate into solution 1 under low-speed stirring and continue stirring for 15 minutes to obtain solution 2.

[0076] 3. Slowly add talcum powder to solution 2 and continue stirring for more than 1 hour to prepare an isolation layer coating solution with a concentration of about 8.5% (w / w).

[0077] 4. Start the high-efficiency coating machine, preheat the machine empty, and when the exhaust temperature reaches 25°C, take the prepared plain tablets and place them in the high-efficiency coating machine, and randomly sample and weigh them. Adjust the atomization and fan pressure to 0.1-0.4Mpa, control the inlet temperature to 25°C during the coating process, the peristaltic pump speed to 1-5 rpm, the pot speed to 4-10 rpm, and coat the isolation layer. The weight gain of the isolation layer is between 3.0 and 6.0%. After the coating is completed, increase the inlet temperature to 40°C, continue drying for 30 minutes, and take out the tablets; after the coating is completed, take samples to test the properties and content of the isolation tablets to obtain dimethyl fumarate isolation tablets.

[0078] In the process of preparing the dimethyl fumarate isolation tablets in Example 5-8, the product appearance, coating film formation, and tablet content after coating were monitored. The process monitoring results are shown in Table 4.

[0079] Table 4 Monitoring and test results of the preparation process of isolation tablets of Examples 5-8 (theoretical coating weight gain 4.5%)

[0080]

[0081] The above results show that Examples 5 and 6 can complete the coating under the condition of an inlet air temperature of 25°C, and the content loss of the prepared isolation film meets the requirements; Examples 7 and 8 cannot complete the coating under the condition of an inlet air temperature of 25°C, and the inlet air temperature needs to be increased to above 30°C to complete the coating. The prepared isolation film has a large sublimation loss and can no longer meet the requirements.

[0082] Example 9-12 Preparation of Dimethyl Fumarate Enteric-coated Capsules

[0083] The isolation tablet prepared in Example 5 was enteric coated, and the formula of the enteric layer coating material is shown in Table 5.

[0084] Table 5 Enteric coating material prescription (unit: mg)

[0085]

[0086] The preparation process of the dimethyl fumarate enteric-coated capsules of Examples 9-12 is as follows:

[0087] 1. Take 10 times the weight of the prescribed amount of polyethylene glycol 4000 and place it in a stainless steel barrel. Slowly add polyethylene glycol 4000 and continue stirring until it dissolves to obtain a polyethylene glycol 4000 aqueous solution (solution 1) for later use.

[0088] 2. Take purified water 10 times the weight of the prescribed amount of talcum powder in a stainless steel barrel, slowly add the talcum powder into the purified water, continue stirring for more than 30 minutes after the addition is completed, and homogenize the stirred suspension using a high-speed homogenizer for more than 3 minutes. The speed of the homogenizer is 8000r / min to obtain a talcum powder suspension (suspension 1) for standby use.

[0089] 3. Add solution 1 to suspension 1, stir for more than 20 minutes, continue to slowly add the prescribed amount of triethyl citrate, stir for more than 30 minutes to obtain suspension 2, which is set aside.

[0090] 4. Weigh the methacrylic acid-ethyl acrylate copolymer aqueous dispersion and place it in a stainless steel barrel, add the remaining amount of purified water, and stir for more than 30 minutes to obtain a methacrylic acid-ethyl acrylate copolymer aqueous dispersion suspension (suspension 3).

[0091] 5. Slowly add the above suspension 2 into the suspension 3 and continue stirring for more than 60 minutes to obtain the enteric layer coating solution.

[0092] 6. Start the high-efficiency coating machine, preheat the empty machine, and when the exhaust air temperature reaches 30-35°C, take the dimethyl fumarate isolation tablet prepared in Example 5 and place it in the high-efficiency coating machine, and randomly sample and weigh it. Adjust the atomization and fan pressure to 0.1-0.4Mpa, control the inlet temperature to 35°C during the coating process, the peristaltic pump speed to 1-5 rpm, the pot speed to 5-12 rpm, and enteric coating. The enteric layer weight gain is between 10-18%. After the coating is completed, the inlet temperature is increased to 40°C, and the drying is continued for 30 minutes. The tablets are taken out to obtain dimethyl fumarate enteric-coated tablets.

[0093] 7. Spread the enteric-coated tablets evenly on the baking tray, turn on the oven, control the temperature inside the oven to 40-45°C, and the curing time to be no less than 24 hours. After the curing is completed, dimethyl fumarate enteric-coated tablets are obtained.

[0094] 8. The solidified dimethyl fumarate enteric-coated tablets are filled with gelatin hollow capsules to obtain dimethyl fumarate enteric-coated capsules.

[0095] In the process of preparing dimethyl fumarate enteric-coated capsules in Examples 9-12, the appearance of the enteric-coated tablets, the film formation of the enteric coating, the capsule content, and the release of the capsule in the dissolution media of pH 1.0 and pH 6.8 were monitored. The process monitoring results are shown in Table 6.

[0096] Table 6 Monitoring and test results of the preparation process of enteric-coated capsules of Examples 9-12

[0097]

[0098]

[0099] The above results show that Examples 9-12 can all be coated successfully, the appearance of the prepared enteric-coated tablets meets the requirements, and there is no significant loss of content during the coating process; the prepared enteric-coated capsules can meet the technical requirement of less than 10% release in 2h in a hydrochloric acid solution of pH 1.0; after the acid resistance test, the release rate in a phosphate buffer solution of pH 6.8 for 15min is more than 80%. However, when the coating weight gain exceeds 18%, it affects the release of the finished product, and the release rate of Example 11 decreases significantly.

[0100] Unless otherwise defined, the terms used in the present invention have the meanings commonly understood by those skilled in the art.

[0101] The embodiments described in the present invention are for illustrative purposes only and are not intended to limit the scope of protection of the present invention. Those skilled in the art may make various other substitutions, changes and improvements within the scope of the present invention. Therefore, the present invention is not limited to the above embodiments, but is only limited by the claims.

Claims

1. A dimethyl fumarate enteric-coated tablet, comprising, from inside to outside, a dimethyl fumarate tablet, a separation layer and an enteric-coated layer, characterized in that: The coating material for the isolation layer is a mixture of hydroxypropyl cellulose, methacrylic acid-methyl methacrylate copolymer 1:1, talcum powder, and triethyl citrate in a mass ratio of 5-8: 2-4: 0.5-1.5: 0.5-1.5, wherein the hydroxypropyl cellulose is selected from hydroxypropyl cellulose EF, and the temperature of the coating material of the isolation layer does not exceed 25°C during the coating process; or the hydroxypropyl cellulose is selected from hydroxypropyl cellulose LF, and the temperature of the coating material of the isolation layer does not exceed 28°C during the coating process.

2. The dimethyl fumarate enteric-coated tablets according to claim 1, characterized in that The weight of the isolation layer is 3-6% of the weight of the dimethyl fumarate tablet.

3. The dimethyl fumarate enteric-coated tablets according to claim 1, characterized in that The isolation layer is formed by the following process: using anhydrous ethanol to prepare a suspension with a concentration of 5-10 wt%, and using the suspension to coat the dimethyl fumarate tablets.

4. The dimethyl fumarate enteric-coated tablets according to claim 1, characterized in that The dimethyl fumarate tablet comprises, by mass percentage, 35-70% of dimethyl fumarate, 15-45% of a diluent, 5-15% of a disintegrant, 6-15% of a glidant and 0.5-1.5% of a lubricant.

5. The dimethyl fumarate enteric-coated tablets according to claim 4, characterized in that The dimethyl fumarate tablet comprises 50-60% of dimethyl fumarate, 20-35% of a diluent, 6-10% of a disintegrant, 6-10% of a glidant and 0.5-1% of a lubricant by mass percentage.

6. The dimethyl fumarate enteric-coated tablets according to claim 4, characterized in that The diluent is selected from one or more of silicified microcrystalline cellulose, spray-dried lactose, microcrystalline cellulose, and mannitol; and / or The disintegrant is selected from one or more of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, and cross-linked polyvinylpyrrolidone XL-10; and / or The glidant is selected from one or more of silicon dioxide, talc, and sodium lauryl sulfate; and / or The lubricant is selected from one or more of magnesium stearate, sodium stearyl fumarate and sodium glycinate.

7. The dimethyl fumarate enteric-coated tablets according to claim 4, characterized in that The diluent is selected from a mixture of silicified microcrystalline cellulose and microcrystalline cellulose KG1000 in a mass ratio of 4 to 6: 1; and / or The disintegrant is selected from cross-linked carboxymethyl cellulose sodium; and / or The glidant is selected from a mixture of talc and silicon dioxide in a mass ratio of 1:1 to 1.5; and / or The lubricant is selected from magnesium stearate.

8. The dimethyl fumarate enteric-coated tablets according to claim 4, characterized in that: The dimethyl fumarate tablets are formed by the following process: the dimethyl fumarate API is crushed to a particle size distribution d(90) <200 μm, and then the crushed dimethyl fumarate API is mixed with the glidant, diluent, disintegrant and lubricant and tabletted.

9. The dimethyl fumarate enteric-coated tablets according to claim 8, characterized in that: The dimethyl fumarate tablets are formed by the following process: the dimethyl fumarate API is crushed to a particle size distribution of d (90) < 200 μm, then the crushed dimethyl fumarate API is mixed with the glidant to obtain a mixture 1, then the mixture 1 is mixed with the diluent and the disintegrant to obtain a mixture 2, then the mixture 2 is mixed with the lubricant to obtain a mixture 3, and finally the mixture 3 is tableted.

10. The dimethyl fumarate enteric-coated tablets according to claim 9, characterized in that: The dimethyl fumarate raw material is crushed by a hammer mill and is stored at a temperature below 8° C. until it is consistent with the ambient temperature before crushing.

11. The dimethyl fumarate enteric-coated tablets according to claim 8, characterized in that The tablet has a tablet hardness of 20 to 40 kgf, a single tablet weight of 7 to 10 mg, and a diameter of 1.5 to 3 mm.

12. The dimethyl fumarate enteric-coated tablets according to claim 1, characterized in that The coating material for the enteric layer is a mixture of methacrylic acid-ethyl acrylate copolymer aqueous dispersion L30D-55, talc, triethyl citrate, and polyethylene glycol 4000 in a mass ratio of 13-18: 1-3: 0.5-1.5: 0.05-0.

15.

13. The dimethyl fumarate enteric-coated tablets according to claim 12, characterized in that: The weight of the enteric layer is 10-18% of the weight of the dimethyl fumarate tablet after being coated with the isolation layer.

14. The dimethyl fumarate enteric-coated tablets according to claim 12, characterized in that: The enteric layer is formed by the following process: using purified water to prepare the coating material for the enteric layer into a suspension with a concentration of 14 to 17 wt%, using the suspension to coat the dimethyl fumarate tablets coated with the isolation layer, and after coating, curing in a dry heat environment at 40 to 60° C. for 24 to 48 hours.

15. The dimethyl fumarate enteric-coated tablets according to claim 14, characterized in that: After coating, cure in a dry heat environment at 40-45°C for 24-30 hours.

16. A dimethyl fumarate enteric-coated capsule, comprising a capsule shell and a filling in the capsule shell, characterized in that: The filler is the dimethyl fumarate enteric-coated tablets according to any one of claims 1 to 15.

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