Apremilast tablet and preparation method thereof

Abstract

The invention discloses an Apremilast tablet and a preparation method thereof, and belongs to the field of medicine. The invention disperses Apremilast in a low eutectic solvent solution of panthenol-citric acid, and adds choline chloride to further assist in dispersion to form a dispersion; then the dispersion, filler, and disintegrant are mixed according to specific steps to obtain a tablet core; finally, a hydroxypropyl cellulose solution is used to coat the tablet core to obtain an Apremilast tablet. The Apremilast tablet prepared by the present invention has few ingredients, a simple preparation process, and good effects.

Description

Technical Field

[0001] The invention relates to an apremilast tablet and a preparation method thereof, and belongs to the field of medicine. Background Art

[0002] Apremilast is a small molecule phosphodiesterase-4 (PDE-4) inhibitor that can regulate the effects of intracellular pro-inflammatory and anti-inflammatory factors, reduce joint swelling and improve the physiological function of joints. The raw material of Apremilast is a white to off-white crystalline powder with a melting point of 153.0℃-156.0℃. It is almost non-hygroscopic, easily soluble in acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide, very slightly soluble in methanol, and almost insoluble in water, ethanol, isopropanol, and methyl tert-butyl ether. It is a typical poorly soluble drug; its dissolution rate limits the absorption of the drug in the body, further affecting the oral bioavailability of the drug.

[0003] Currently, apremilast is routinely prepared as tablets for use;

[0004] For example, CN107115310A discloses an oral solid preparation of Apremilast and a preparation method thereof, wherein the oral solid preparation of Apremilast contains active pharmaceutical ingredients, fillers, disintegrants, lubricants and coating materials; however, the stability is poor, and the preparation has many ingredients and is complicated to operate;

[0005] CN104523574A discloses an apremilast solid dispersion and a preparation method thereof, wherein the apremilast solid dispersion is obtained by uniformly dispersing apremilast in a molten auxiliary material and then rapidly cooling it; however, the temperature in the preparation method is difficult to control and is not convenient for actual large-scale production operations;

[0006] CN105343025A discloses an oral apremilast preparation and a preparation method thereof, wherein the apremilast tablet is prepared by a wet granulation process; however, the preparation process is complicated to operate and has a high production cost;

[0007] CN104546831A discloses a pharmaceutical composition containing Apremilast, wherein the pharmaceutical composition is prepared by combining Apremilast with cyclodextrin or a cyclodextrin derivative to form an inclusion compound; however, cyclodextrin is easily soluble in water, so that the release rate of Apremilast is high and it is difficult for Apremilast to work for a long time;

[0008] CN110548015A discloses an Apremilast tablet and a preparation method thereof, wherein the Apremilast tablet is prepared by sieving active ingredients and excipients, mixing them uniformly, pressing them into tablets, and coating them; however, the Apremilast tablet has poor stability and is difficult to exert its effect for a long time.

[0009] Moreover, Apremilast is a common tablet, and the dosage for long-term use is 30 mg twice a day, 12 hours apart. However, Apremilast sustained-release tablets can change the frequency of medication to once a day, making patients more compliant, while also reducing fluctuations in blood drug concentrations, which can greatly reduce side effects during medication.

[0010] In addition, the gastrointestinal side effects of apremilast are more severe;

[0011] Therefore, finding an apremilast tablet with simple ingredients, easy operation, longer duration of action, improved water solubility, and sustained-release properties is an urgent problem that needs to be solved. Summary of the invention

[0012] In order to solve the above problems, the present invention disperses Apremilast in a low eutectic solvent solution of panthenol-citric acid, and adds choline chloride to further assist dispersion to form a dispersion; then the dispersion, filler, and disintegrant are mixed according to specific steps to obtain a tablet core; finally, a hydroxypropyl cellulose solution is used to coat the tablet core to obtain an Apremilast tablet. The Apremilast tablet prepared by the present invention has simple ingredients and a simple preparation process; and has a good sustained-release effect, can be slowly released over a long period of time, can prolong the drug's action time, and reduce the number of medications, and the blood drug concentration fluctuates less, which helps to reduce the toxic and side effects of the drug.

[0013] The first object of the present invention is to provide a method for preparing Apremilast tablets, comprising the following steps:

[0014] (1) mixing panthenol and citric acid uniformly, cooling, and obtaining a low eutectic solvent; adding water to the low eutectic solvent and mixing, and obtaining a low eutectic solvent solution;

[0015] (2) adding apremilast and choline chloride to a deep eutectic solvent solution, stirring at high speed, and drying to obtain a dispersion;

[0016] (3) uniformly mixing a portion of the dispersion, a filler, and a disintegrant to obtain a mixture;

[0017] (4) adding the remaining dispersion to the mixture and continuing to mix to obtain a mixed batch;

[0018] (5) granulating and sizing the mixed ingredients, sieving, and tableting to obtain tablet cores;

[0019] (6) Prepare a hydroxypropyl cellulose solution and coat the tablet cores to obtain apremilast tablets.

[0020] In one embodiment of the present invention, the molar ratio of panthenol to citric acid in step (1) is 0.5-1.5:2.

[0021] In one embodiment of the present invention, the uniform mixing in step (1) is performed at 80-90° C. and 200-500 rpm for 1-3 hours.

[0022] In one embodiment of the present invention, the mass ratio of the low eutectic solvent to water in step (1) is 1:3-6.

[0023] In one embodiment of the present invention, the molar ratio of choline chloride in step (2) to citric acid in step (1) is 0.5-1.5:2.

[0024] In one embodiment of the present invention, the mass ratio of apremilast to the low eutectic solvent solution in step (2) is 10:10-15.

[0025] In one embodiment of the present invention, the high-speed stirring in step (2) is high-speed stirring at 5000-10000 rpm for 10-20 min.

[0026] In one embodiment of the present invention, the drying in step (2) is performed so that the moisture content is below 5%.

[0027] In one embodiment of the present invention, the filler in step (3) is a mixture of microcrystalline cellulose and calcium hydrogen phosphate, and the mass ratio of the two is 1-2:1-2.

[0028] In one embodiment of the present invention, the disintegrant in step (3) is hydroxypropyl cellulose.

[0029] In one embodiment of the present invention, the mass ratio of the dispersion, filler and disintegrant in step (3) is 20-30:20-40:10-20; the mass ratio of the dispersion in step (3) and step (4) is 1-2:1.

[0030] In one embodiment of the present invention, the uniform mixing in step (3) is performed by high-speed stirring at 1000-3000 rpm for 10-20 min.

[0031] In one embodiment of the present invention, the continued mixing in step (4) is high-speed stirring at 2000-4000 rpm for 10-20 min.

[0032] In one embodiment of the present invention, the mesh size of the granulation and granulation in step (5) can pass through a 10-80 mesh sieve.

[0033] In one embodiment of the present invention, the hydroxypropyl cellulose solution in step (6) is a hydroxypropyl cellulose aqueous solution with a mass concentration of 10-20%.

[0034] In one embodiment of the present invention, the temperature during the coating process in step (6) is controlled at 35-42°C.

[0035] In one embodiment of the present invention, after the coating in step (6) is completed, the tablet core increases in weight by 1-2% (mass percentage).

[0036] The second object of the present invention is the Apremilast tablets prepared by the method described in the present invention.

[0037] The beneficial effects of the present invention are as follows:

[0038] (1) The apremilast tablets prepared by the present invention have fewer ingredients, simple preparation process, and good sustained-release effect.

[0039] (2) The apremilast tablets prepared by the present invention have low irritation and are more acceptable to humans.

[0040] (3) The low eutectic solvent solution of panthenol-citric acid and the addition of choline chloride in the apremilast tablets prepared by the present invention further increase the dispersibility and solubility of apremilast. DETAILED DESCRIPTION

[0041] The preferred embodiments of the present invention are described below. It should be understood that the embodiments are for better explaining the present invention and are not used to limit the present invention.

[0042] Test method:

[0043] 1. Friability:

[0044] Check according to the Appendix of Part 2 of the 2010 edition of the Chinese Pharmacopoeia. For tablets weighing 0.65g or less, take a number of tablets to make the total weight about 6.5g; for tablets weighing more than 0.65g, take 10 tablets. Use a hair dryer to blow away the fallen powder, weigh accurately, and rotate it in a cylinder 100 times. Take it out, remove the powder in the same way, weigh accurately, and the weight loss shall not exceed 1%, and no broken, cracked or crushed tablets shall be detected. The specific calculation formula is as follows:

[0045]

[0046] 2. Hardness:

[0047] Take a tablet and place it in the jaws of the tablet hardness tester. Slowly turn the rocker to increase the pressure applied to the tablet until the tablet is cracked, thereby measuring the hardness of the tablet. A total of 10 tablets need to be checked.

[0048] 3. Angle of repose:

[0049] Also known as the natural slope angle, it refers to the maximum angle that the free surface of the particle accumulation layer can form in a static state. It can indirectly measure the friction of the powder and characterize the fluidity of the powder through the angle of repose.

[0050] 4. Dissolution:

[0051] Take Apremilast tablets, according to the dissolution and release determination method (Chinese Pharmacopoeia 2015 Edition Part Four General Rules 0931 Second Method), use 900mL of pH 1.0 hydrochloric acid solution containing 0.5% (w / v) Tween 80 (measure 9mL of concentrated hydrochloric acid, dilute to 1000mL with water, that is) as the dissolution medium, the speed is 75 revolutions per minute, operate according to the law, sample 10mL at 5, 10, 15, 20, and 24h, and add isothermal and equal volume medium in time. After the sample is filtered with a microporous filter membrane (using a hydrophilic filter material), the filtrate is taken as the test solution, and the high performance liquid chromatography (HPLC) is used for analysis and determination to obtain the dissolution amount of Apremilast in each tablet.

[0052] The raw materials used in the embodiment:

[0053] Apremilast: 98%, CAS: 608141-41-9;

[0054] Choline chloride: 98%, CAS: 67-48-1;

[0055] Panthenol: 98%, D-panthenol, medical CP grade, CAS: 81-13-0;

[0056] Citric acid: 99.5%, anhydrous citric acid, CAS: 77-92-9;

[0057] Microcrystalline cellulose: CAS: 9004-34-6;

[0058] Dicalcium phosphate: anhydrous calcium phosphate, 98%, CAS: 7757-93-9;

[0059] Hydroxypropyl cellulose: low degree of substitution, CAS: 9004-64-2;

[0060] All raw materials are of pharmaceutical grade and can be purchased commercially.

[0061] Tablet compression: Use 6mm round punch die, unit tablet weight 100mg.

[0062] Example 1

[0063] A method for preparing Apremilast tablets comprises the following steps:

[0064] (1) mixing panthenol and citric acid at a molar ratio of 1:2 at 80° C. and 300 rpm for 2 h, and cooling to obtain a low eutectic solvent; adding water to the low eutectic solvent, with a mass ratio of the low eutectic solvent to water being 1:5, and mixing at room temperature and 300 rpm for 30 min to obtain a low eutectic solvent solution;

[0065] (2) adding apremilast and choline chloride to a low eutectic solvent solution, stirring at a high speed of 8000 rpm for 20 min, and drying to obtain a dispersion having a water content of 2%; wherein the molar ratio of choline chloride to citric acid is 1:2; and the mass ratio of apremilast to the low eutectic solvent solution is 10:15;

[0066] (3) stirring a portion of the dispersion, a mixture of microcrystalline cellulose and calcium hydrogen phosphate (mass ratio 1:1), and hydroxypropyl cellulose at a mass ratio of 15:40:20 at 3000 rpm for 15 minutes to obtain a mixture;

[0067] (4) adding the remaining dispersion (the same amount as in step (3)) to the mixture, and continuing to stir at 4000 rpm for 10 min to obtain a mixed batch;

[0068] (5) granulating and sizing the mixed ingredients, sieving through 50 mesh, and tableting to obtain tablet cores;

[0069] (6) A 15% mass concentration hydroxypropyl cellulose aqueous solution was prepared and coated on the tablet cores at 38° C. with a weight gain of 1% to obtain apremilast tablets.

[0070] Example 2

[0071] The mass ratio of a portion of the dispersion, the mixture of microcrystalline cellulose and calcium hydrogen phosphate (mass ratio 1:1), and hydroxypropyl cellulose in step (3) of Example 1 was adjusted to 10:40:20, and the rest was kept the same as Example 1 to obtain Apremilast tablets.

[0072] Example 3

[0073] The coating weight gain in step (6) of Example 1 was adjusted to 2%, and the other steps were kept the same as in Example 1 to obtain Apremilast tablets.

[0074] Example 4

[0075] The molar ratio of panthenol to citric acid in step (1) of Example 1 was adjusted to 1:1; the other conditions were kept the same as in Example 1 to obtain Apremilast tablets.

[0076] Comparative Example 1

[0077] Steps (1) and (2) of Example 1 were omitted, and Apremilast was directly used in step (3). The rest of the steps were the same as in Example 1.

[0078] Comparative Example 2

[0079] The choline chloride in step (2) of Example 1 was omitted, and the rest was the same as in Example 1.

[0080] Comparative Example 3

[0081] The betaine in step (2) of Example 1 was adjusted, and the rest was the same as Example 1.

[0082] Comparative Example 4

[0083] The panthenol in step (1) of Example 1 was adjusted to choline chloride, and the choline chloride in step (2) was omitted. The rest was the same as in Example 1.

[0084] Comparative Example 5

[0085] The citric acid in step (1) of Example 1 was adjusted to lactic acid, and the rest remained the same as in Example 1.

[0086] Comparative Example 6

[0087] The mixture of microcrystalline cellulose and calcium hydrogen phosphate (mass ratio 1:1) in step (3) of the embodiment was adjusted to microcrystalline cellulose, and the rest was consistent with that in embodiment 1.

[0088] Comparative Example 7

[0089] The mixture of microcrystalline cellulose and calcium hydrogen phosphate (mass ratio 1:1) in step (3) of the embodiment was adjusted to calcium hydrogen phosphate, and the rest was consistent with that in embodiment 1.

[0090] Comparative Example 8

[0091] Combine steps (3) and (4) of Example 1, add the dispersion all at once, and keep the rest the same as Example 1.

[0092] Comparative Example 9

[0093] Step (6) of Example 1 is omitted, and the rest is the same as Example 1.

[0094] Comparative Example 10

[0095] The hydroxypropyl cellulose in step (6) of Example 1 was adjusted to gelatin, and the rest remained the same as Example 1.

[0096] The obtained Apremilast tablets were subjected to performance tests, and the test results were as follows:

[0097] Table 1 Properties of tablets

[0098] example hardness Friability (%) Angle of repose(°) Example 1 6.56 0.05 24.5 Example 2 6.54 0.04 23.3 Example 3 6.72 0.03 26.3 Example 4 6.52 0.07 27.3 Comparative Example 1 10.89 0.36 46.7 Comparative Example 2 9.42 0.24 36.4 Comparative Example 3 7.12 0.13 28.4 Comparative Example 4 8.20 0.17 30.5 Comparative Example 5 8.13 0.18 31.5 Comparative Example 6 7.34 0.10 35.2 Comparative Example 7 7.57 0.11 35.8 Comparative Example 8 9.80 0.28 42.1 Comparative Example 9 5.23 0.16 22.6 Comparative Example 10 6.12 0.10 27.4

[0099] Table 2 Dissolution amount (%) data

[0100]

[0101]

[0102] Note: “-” represents complete dissolution.

[0103] Although the present invention has been disclosed as above in the form of a preferred embodiment, it is not intended to limit the present invention. Anyone familiar with this technology can make various changes and modifications without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention should be based on the definition of the claims.

Claims

1. A method for preparing Apremilast tablets, characterized in that: The steps include: (1) mixing panthenol and citric acid uniformly, cooling, and obtaining a low eutectic solvent; adding water to the low eutectic solvent and mixing, and obtaining a low eutectic solvent solution; (2) adding apremilast and choline chloride to a deep eutectic solvent solution, stirring at high speed, and drying to obtain a dispersion; (3) uniformly mixing a portion of the dispersion, a filler, and a disintegrant to obtain a mixture; (4) adding the remaining dispersion to the mixture and continuing to mix to obtain a mixed batch; (5) granulating and sizing the mixed ingredients, sieving, and tableting to obtain tablet cores; (6) Prepare hydroxypropyl cellulose solution and coat the tablet core to obtain Apremilast tablets Wherein, the molar ratio of panthenol to citric acid in step (1) is 0.5-1.5:2; the mass ratio of the low eutectic solvent to water in step (1) is 1:3-6; The molar ratio of choline chloride in step (2) to citric acid in step (1) is 0.5-1.5:2; the mass ratio of apremilast to the low eutectic solvent solution in step (2) is 5-10:10-15; The filler in step (3) is a mixture of microcrystalline cellulose and calcium hydrogen phosphate, and the mass ratio of the two is 1-2:1-2; the mass ratio of the dispersion, filler, and disintegrant in step (3) is 20-30:20-40:10-20; the mass ratio of the dispersion in step (3) and step (4) is 1-2:1; The hydroxypropyl cellulose solution in step (6) is a hydroxypropyl cellulose aqueous solution with a mass concentration of 10-20%.

2. The method according to claim 1, characterized in that In step (2), the high-speed stirring is 5000-10000 rpm for 10-20 min.

3. The method according to claim 1, characterized in that The drying in step (2) is performed so that the moisture content is below 5%.

4. The method according to claim 1, characterized in that: The uniform mixing in step (3) is carried out by high-speed stirring at 1000-3000 rpm for 10-20 min.

5. The method according to claim 1, characterized in that: In step (3), the disintegrant is hydroxypropyl cellulose.

6. The method according to claim 1, characterized in that In step (4), the mixing is continued by stirring at a high speed of 2000-4000 rpm for 10-20 min.

7. The method according to claim 1, characterized in that The mesh size of the granulation and granulation in step (5) can pass through a 10-80 mesh sieve.

8. The method according to claim 1, characterized in that The hydroxypropyl cellulose solution in step (6) is a hydroxypropyl cellulose aqueous solution with a mass concentration of 10-20%.

9. The method according to claim 1, characterized in that: During the coating process in step (6), the temperature is controlled at 35-42°C.

10. The method according to claim 1, characterized in that After the coating in step (6) is completed, the tablet core gains weight by 1-2% by weight.

11. Apremilast tablets prepared by the method according to any one of claims 1 to 10.

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