PHARMACEUTICAL COMPOSITION COMPRISING TBN, OR SALT OR HYDRATE THEREOF, AND PREPARATION METHOD THEREOF

Abstract

The present invention discloses a pharmaceutical composition comprising TBN, or a salt or a hydrate thereof, and a preparation method therefor. The pharmaceutical composition comprises (1) a tablet core comprising the active ingredient TBN or a pharmaceutically acceptable salt or hydrate thereof and an alkalizing agent; and (2) an enteric layer outside the tablet core, comprising an opaquer and a coating material. The pharmaceutical composition has the enteric layer with good film-forming ability, which improves the bioavailability of TBN in the body; and is useful in the treatment of diseases caused by overproduction of free radicals/thrombosis in clinic.

Claims

1. A pharmaceutical composition comprising TBN, or a salt or a hydrate thereof, the pharmaceutical composition having: (1) a tablet core comprising the active ingredient TBN or a pharmaceutically acceptable salt or hydrate thereof and an alkalizing agent; and (2) an enteric layer outside the tablet core, comprising an opaquer and a coating material, wherein the enteric layer accounts for 0.5-20% by weight.

2. The pharmaceutical composition according to claim 1, wherein the tablet core further comprises a binder and/or a disintegrant and/or a filler and/or a lubricant; and the enteric layer further comprises a plasticizer and/or an anti-sticking agent.

3. The pharmaceutical composition according to claim 1, wherein an isolation layer comprising a coating and an anti-sticking agent is provided between the tablet core and the enteric layer.

4. The pharmaceutical composition according to claim 1, wherein the alkalizing agent is one or more selected from sodium bicarbonate, magnesia and magnesium carbonate.

5. The pharmaceutical composition according to claim 1, wherein in the enteric layer, the opaquer is titania; and the coating material is one or more of methacrylic acid-ethyl acrylate copolymer, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit L30D-55, Eudragit L100, and Eudragit NE30D, where the weight ratio of the opaquer to the coating material is (0.5-2.5):(5-20).

6. The pharmaceutical composition according to claim 2, wherein the binder is one or more selected from hydroxypropyl cellulose, Polyvidone K30, hydroxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and polyvinylpyrrolidone, where the weight ratio of the active ingredient to the binder is (90-110):(5-30); the disintegrant is one or more selected from Crospovidone, Croscarmellose sodium, Carboxymethyl starch sodium, sodium hydroxypropyl starch or low-substituted hydroxypropyl cellulose, where the weight ratio of the active ingredient to the disintegrant is (90-110):(3-30); the filler is one or more selected from mannitol, microcrystalline cellulose, lactose, xylitol, sucrose, glucose, sorbitol, starch, pregelatinized starch, calcium sulfate, calcium carbonate, calcium hydrogen phosphate or light magnesia, where the weight ratio of the active ingredient to the filler is (90-110):(60-200); and the lubricant is one or more selected from magnesium stearate, stearic acid, talc, hydrogenated vegetable oil, glyceryl behenate or micronized silica gel, where the weight ratio of the active ingredient to the lubricant is (90-110):(0.2-2).

7. The pharmaceutical composition according to claim 1, wherein the tablet core comprises the active ingredient TBN or a pharmaceutically acceptable salt or hydrate thereof, the alkalizing agent, the binder, the disintegrant, the filler and the lubricant, where the weight ratio of the active ingredient:alkalizing agent:binder:disintegrant:filler:lubricant is (90-110):(5-30):(5-30):(3-30):(60-200):(0.2-2).

8. The pharmaceutical composition according to claim 2, wherein the plasticizer in the enteric layer is one or more of triethyl citrate, PEG4000, PEG6000, triethyl acetylcitrate, and polysorbate-80; the anti-sticking agent in the enteric layer is one or more of talc, glyceryl monostearate, and micronized silica gel; the coating material in the isolation layer is one or more of hydroxypropyl cellulose or ethyl cellulose, and the anti-sticking agent in the isolation layer is one or more of talc, magnesia, glyceryl monostearate, and micronized silica gel, where the weight ratio of the coating material to the anti-sticking agent in the isolation layer is (1-10):1; and the moisture barrier is Opadry.

9. A method for preparing a pharmaceutical composition comprising TBN, or a salt or a hydrate thereof, the method comprising the following steps: (1) sieving the active ingredient TBN or a pharmaceutically acceptable salt or hydrate thereof, and an alkalizing agent and/or a binder and/or a disintegrant and/or a filler, directly mixing or mixing and then granulating, optionally mixing with a lubricant, and tableting to obtain tablet cores; and (2) coating the tablet core in Step (1) with an enteric layer at 40-50° C. and removing to obtain a TBN enteric-coated tablet.

10. A method of treating a neurological disease, a cardiovascular disease, or a cerebrovascular disease comprising administering the pharmaceutical composition according to claim 1 to a subject in need thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0050] FIG. 1 shows the drug concentration-time curve after oral administration of enteric-coated tablets to beagle dogs.

[0051] FIG. 2 shows the drug concentration-time curve after oral administration of TBN (API) to beagle dogs.

DETAILED DESCRIPTION

[0052] The following examples are provided for a better understanding of the present invention; however, the present invention is not limited thereto. The methods given in examples below are all conventional methods, unless it is otherwise stated. Test materials used in the following examples are commercially available, unless otherwise specified.

Example 1

[0053] TBN (API), mannitol, pregelatinized starch, Crospovidone, sodium bicarbonate and magnesium stearate were sieved through a 40-mesh screen for later use. 100 g of TBN (API), 70 g of mannitol, 70 g of pregelatinized starch, 7.5 g of Polyvidone K30, 5 g of Crospovidone, and 10 g of sodium bicarbonate were weighed, and mixed for 30 min in a hopper mixer in the laboratory. Then, 1 g of magnesium stearate was added and mixed for another 1 min. The resulting material was directly tableted, to obtain 1000 tablet cores with a specification of 100 mg and an average tablet weight of 0.2635 g.

Example 2

[0054] TBN (API), mannitol, pregelatinized starch, Crospovidone, sodium bicarbonate, and magnesium stearate were sieved through a 40-mesh screen for later use. 100 g of TBN (API), 70 g of mannitol, 70 g of pregelatinized starch, 7.5 g of Polyvidone K30, 5 g of Crospovidone, and 20 g of sodium bicarbonate were weighed, and mixed for 30 min in a hopper mixer in the laboratory. Then, 1 g of magnesium stearate was added and mixed for another 1 min. The resulting material was directly tableted, to obtain 1000 tablet cores with a specification of 100 mg and an average tablet weight of 0.2735 g.

Example 3

[0055] TBN (API), mannitol, pregelatinized starch, Crospovidone, magnesia, and magnesium stearate were sieved through a 40-mesh screen for later use. 100 g of TBN (API), 70 g of mannitol, 70 g of pregelatinized starch, 7.5 g of Polyvidone K30, 5 g of Crospovidone, and 20 g of magnesia were weighed, and mixed for 30 min in a hopper mixer in the laboratory. Then, 1 g of magnesium stearate was added and mixed for another 1 min. The resulting material was directly tableted, to obtain 1000 tablet cores with a specification of 100 mg and an average tablet weight of 0.2735 g.

Example 4

[0056] TBN (API), mannitol, pregelatinized starch, Crospovidone, magnesium carbonate and magnesium stearate were sieved through a 40-mesh screen for later use. 100 g of TBN (API), 70 g of mannitol, 70 g of pregelatinized starch, 7.5 g of Polyvidone K30, 5 g of Crospovidone, and 20 g of magnesium carbonate were weighed, and mixed for 30 min in a hopper mixer in the laboratory. Then, 1 g of magnesium stearate was added and mixed for another 1 min. The resulting material was directly tableted, to obtain 1000 tablet cores with a specification of 100 mg and an average tablet weight of 0.2735 g.

Example 5

[0057] TBN (API), mannitol, pregelatinized starch, Crospovidone, sodium bicarbonate and magnesium stearate were sieved through a 40-mesh screen for later use. 100 g of TBN (API), 70 g of mannitol, 70 g of pregelatinized starch, 15 g of Polyvidone K30, 5 g of Crospovidone, and 20 g of sodium bicarbonate were weighed, and mixed for 30 min in a hopper mixer in the laboratory. Then, 1 g of magnesium stearate was added and mixed for another 1 min. The resulting material was directly tablet, to obtain 1000 tablet cores with a specification of 100 mg and an average tablet weight of 0.281 g.

Example 6

[0058] TBN (API), mannitol, pregelatinized starch, Crospovidone, sodium bicarbonate and magnesium stearate were sieved through a 40-mesh screen for later use. 100 g of TBN (API), 60 g of mannitol, 60 g of pregelatinized starch, 30 g of Polyvidone K30, 5 g of Crospovidone, and 20 g of sodium bicarbonate were weighed, and mixed for 30 min in a hopper mixer in the laboratory. Then, 1 g of magnesium stearate was added and mixed for another 1 min. The resulting material was directly tablet, to obtain 1000 tablet cores with a specification of 100 mg and an average tablet weight of 0.276 g.

Example 7

[0059] TBN (API), mannitol, hydroxypropyl cellulose, Crospovidone, sodium bicarbonate and magnesium stearate were sieved through a 40-mesh screen for later use. 300 g of TBN (API), 231 g of mannitol, 75 g of hydroxypropyl cellulose, 51 g of Crospovidone, and 60 g of sodium bicarbonate were weighed, and mixed for 30 min in a hopper mixer in the laboratory. Then, 3 g of magnesium stearate was added and mixed for another 1 min. The resulting material was directly tableted, to obtain 1000 tablet cores with a specification of 300 mg and an average tablet weight of 0.72 g.

Example 8

[0060] TBN (API), mannitol, hydroxypropyl cellulose, Crospovidone, sodium bicarbonate and magnesium stearate were sieved through a 40-mesh screen for later use. 300 g of raw TBN (API), 248.4 g of mannitol, 57.6 g of hydroxypropyl cellulose, 51 g of Crospovidone, and 60 g of sodium bicarbonate were weighed, and mixed for 30 min in a hopper mixer in the laboratory. Then, 3 g of magnesium stearate was added and mixed for another 1 min. The resulting material was directly tableted, to obtain 1000 tablet cores with a specification of 300 mg and an average tablet weight of 0.72 g.

Example 9

[0061] TBN (API), mannitol, hydroxypropyl cellulose, Crospovidone, sodium bicarbonate and magnesium stearate were sieved through a 40-mesh screen for later use. 300 g of TBN (API), 248.4 g of mannitol, 57.6 of hydroxypropyl cellulose, 51 g of Crospovidone, and 60 g of sodium bicarbonate were weighed, mixed for 30 min in a hopper mixer in the laboratory, and dry granulated. Then, 3 g of magnesium stearate was added and mixed for another 1 min, to obtain 1000 tablet cores with a specification of 300 mg and an average tablet weight of 0.72 g.

Example 10

[0062] TBN (API), mannitol, Carboxymethyl starch sodium, sodium bicarbonate, hydroxypropyl cellulose and magnesium stearate were sieved through a 40-mesh screen for later use. 300 g of TBN (API), 272 g of mannitol, 75 g of hydroxypropyl cellulose, 40 g of Carboxymethyl starch sodium, and 60 g of sodium bicarbonate were weighed, and mixed for 30 min in a hopper mixer in the laboratory. Then, 3 g of magnesium stearate was added and mixed for another 1 min. The resulting material was directly tableted, to obtain 1000 tablet cores with a specification of 300 mg and an average tablet weight of 0.75 g.

Example 11

[0063] TBN (API), mannitol, Crospovidone, sodium bicarbonate, hydroxypropyl cellulose and magnesium stearate were sieved through a 40-mesh screen for later use. 300 g of TBN (API), 272 g of mannitol, 75 g of hydroxypropyl cellulose, 40 g of Crospovidone, and 60 g of sodium bicarbonate were weighed, and mixed for 30 min in a hopper mixer in the laboratory. Then, 3 g of magnesium stearate was added and mixed for another 1 min. The resulting material was directly tableted, to obtain 1000 tablet cores with a specification of 300 mg and an average tablet weight of 0.75 g.

Example 12

[0064] TBN (API), mannitol, Crospovidone, sodium bicarbonate, hydroxypropyl cellulose and magnesium stearate were sieved through a 40-mesh screen for later use. 300 g of TBN (API), 231 g of mannitol, 75 g of hydroxypropyl cellulose, 51 g of Crospovidone, and 60 g of sodium bicarbonate were weighed, and mixed for 30 min in a hopper mixer in the laboratory. Then, 3 g of magnesium stearate was added and mixed for another 1 min. The resulting material was directly tableted, to obtain 1000 tablet cores with a specification of 300 mg and an average tablet weight of 0.72 g.

Example 13

[0065] TBN (API), mannitol, pregelatinized starch, Crospovidone, sodium bicarbonate and magnesium stearate were sieved through a 40-mesh screen for later use. 100 g of TBN (API), 60 g of mannitol, 60 g of pregelatinized starch, 30 g of Polyvidone K30, 5 g of Crospovidone, and 10 g of sodium bicarbonate were weighed, and mixed for 30 min in a hopper mixer in the laboratory. Then, 1 g of magnesium stearate was added and mixed for another 1 min. The resulting material was directly tableted.

[0066] Then the tablet cores were added to a high-efficiency coating machine, and the prepared isolation coating solution containing 4.81 g of hydroxypropyl cellulose, 4.81 g of talc, and 70.55 g of absolute ethanol was added. The isolation layer accounted for 3.62% by weight. Next, a moisture barrier forming solution containing 12.68 g of Opadry, and 66.57 g of pure water was added. The moisture barrier accounted for 4.60% by weight. After that, an enteric coating solution containing 30.76 g of hydroxypropyl methylcellulose phthalate, 2.46 g of triethyl citrate, 1.54 g of titania, 5.42 g of talc, 275.30 g of absolute ethanol, and 68.83 g of pure water was added, and the enteric layer accounted for 10.67% by weight. Thus, TBN enteric-coated tablets were obtained.

Example 14

[0067] TBN (API), mannitol, pregelatinized starch, Crospovidone, sodium bicarbonate and magnesium stearate were sieved through a 40-mesh screen for later use. 100 g of TBN (API), 60 g of mannitol, 60 g of pregelatinized starch, 30 g of Polyvidone K30, 5 g of Crospovidone, and 10 g of sodium bicarbonate were weighed, and mixed for 30 min in a hopper mixer in the laboratory. Then, 1 g of magnesium stearate was added and mixed for another 1 min. The resulting material was directly tableted.

[0068] Then the tablet cores were added to a high-efficiency coating machine, and the prepared isolation coating solution containing 6.73 g of hydroxypropyl cellulose, 4.81 g of talc, and 100.89 g of absolute ethanol was added. The isolation layer accounted for 2.95% by weight. Next, a moisture barrier forming solution containing 9.58 g of Opadry and 50.32 g of pure water was added. The moisture barrier accounted for 3.50% by weight. After that, an enteric coating solution containing 25.74 g of hydroxypropyl methylcellulose phthalate, 2.06 g of triethyl citrate, 1.29 g of titania, 4.70 g of talc, 230.33 g of absolute ethanol, and 57.58 g of pure water was added, and the enteric layer accounted for 9.08% by weight. Thus, TBN enteric-coated tablets were obtained.

Example 15

[0069] TBN (API), mannitol, Crospovidone, sodium bicarbonate, hydroxypropyl cellulose and magnesium stearate were sieved through a 40-mesh screen for later use. 300 g of TBN (API), 248.4 g of mannitol, 57.6 g of hydroxypropyl cellulose, 51 g of Crospovidone, and 60 g of sodium bicarbonate were weighed, mixed for 30 min in a hopper mixer in the laboratory, and granulated. Then, 3 g of magnesium stearate was added and mixed for another 1 min, to obtain tablet cores. Then the tablet cores were added to a high-efficiency coating machine, and the prepared isolation coating solution containing 55.6 g of hydroxypropyl cellulose and 16.4 g of talc was added. The isolation layer accounted for 10% by weight. The composition of the enteric layer was the same as that in Example 24, and the enteric layer accounted for 6% by weight. Thus, TBN enteric-coated tablets were obtained.

Example 16

[0070] TBN (API), mannitol, Crospovidone, sodium bicarbonate, hydroxypropyl cellulose and magnesium stearate were sieved through a 40-mesh screen for later use. 300 g of TBN (API), 248.4 g of mannitol, 57.6 g of hydroxypropyl cellulose, 51 g of Crospovidone, and 60 g of sodium bicarbonate were weighed, mixed for 30 min in a hopper mixer in the laboratory, and granulated. Then, 3 g of magnesium stearate was added and mixed for another 1 min, to obtain tablet cores. Then the tablet cores were added to a high-efficiency coating machine, and the prepared isolation coating solution containing 27.8 g of hydroxypropyl cellulose and 8.2 g of talc was added. The isolation layer accounted for 5% by weight. The composition of the enteric layer was the same as that in Example 24, and the enteric layer accounted for 6% by weight. Thus, TBN enteric-coated tablets were obtained.

Example 17

[0071] TBN (API), mannitol, Crospovidone, sodium bicarbonate and magnesium stearate were sieved through a 40-mesh screen for later use. 100 g of TBN (API), 100 g of mannitol, 10 g of Polyvidone K30, 25 g of Crospovidone, and 60 g of sodium bicarbonate were weighed, and mixed for 30 min in a hopper mixer in the laboratory. Then, 1 g of magnesium stearate was added and mixed for another 1 min. The resulting material was directly tableted.

[0072] Then the tablet cores were added to a high-efficiency coating machine, and the prepared isolation coating solution containing 8.78 g of hydroxypropyl cellulose, 8.78 g of talc, and 128.77 g of absolute ethanol was added. The isolation layer accounted for 5.93% by weight. Next, a moisture barrier forming solution containing 14.49 g of Opadry (81W680001), and 76.07 g of pure water was added. The moisture barrier accounted for 4.62% by weight. After that, an enteric coating solution containing 27.39 g of hydroxypropyl methylcellulose phthalate, 2.19 g of triethyl citrate, 1.37 g of titania, 5.00 g of talc, 245.14 g of absolute ethanol, and 61.29 g of pure water was added, and the enteric layer accounted for 8.35% by weight. Thus, TBN enteric-coated tablets were obtained.

Example 18

[0073] TBN (API), mannitol, Crospovidone, sodium bicarbonate and magnesium stearate were sieved through a 40-mesh screen for later use. 100 g of TBN (API), 100 g of mannitol, 10 g of Polyvidone K30, 25 g of Crospovidone, and 60 g of sodium bicarbonate were weighed, and mixed for 30 min in a hopper mixer in the laboratory. Then, 1 g of magnesium stearate was added and mixed for another 1 min. The resulting material was directly tableted.

[0074] Then the tablet cores were added to a high-efficiency coating machine, and the prepared isolation coating solution containing 8.78 g of hydroxypropyl cellulose, 8.78 g of talc, and 128.77 g of absolute ethanol was added. The isolation layer accounted for 5.93% by weight. Next, a moisture barrier forming solution containing 6.33 g of Opadry (21K58794), 14.88 g of pure water and 84.29 g of absolute ethanol was added. The moisture barrier accounted for 2.02% by weight. After that, an enteric coating solution containing 27.39 g of hydroxypropyl methylcellulose phthalate, 2.19 g of triethyl citrate, 1.37 g of titania, 5.00 g of talc, 245.07 g of absolute ethanol, and 61.27 g of pure water was added, and the enteric layer accounted for 8.56% by weight. Thus, TBN enteric-coated tablets were obtained.

Example 19

[0075] TBN (API), mannitol, Crospovidone, sodium bicarbonate and magnesium stearate were sieved through a 40-mesh screen for later use. 100 g of TBN (API), 100 g of mannitol, 10 g of Polyvidone K30, 25 g of Crospovidone, and 60 g of sodium bicarbonate were weighed, and mixed for 30 min in a hopper mixer in the laboratory. Then, 1 g of magnesium stearate was added and mixed for another 1 min. The resulting material was directly tableted.

[0076] Then the tablet cores were added to a high-efficiency coating machine, and the prepared isolation coating solution containing 8.78 g of hydroxypropyl cellulose, 8.78 g of talc, and 128.77 g of absolute ethanol was added. The isolation layer accounted for 5.93% by weight. Next, a moisture barrier forming solution containing 14.49 g of Opadry, and 76.07 g of pure water was added. The moisture barrier accounted for 4.62% by weight. After that, an enteric coating solution containing 27.39 g of hydroxypropyl methylcellulose phthalate, 2.19 g of triethyl citrate, 1.37 g of titania, 5.00 g of talc, 245.14 g of absolute ethanol, and 61.29 g of pure water was added, and the enteric layer accounted for 8.35% by weight. Thus, TBN enteric-coated tablets were obtained.

Example 20

[0077] TBN (API), mannitol, Crospovidone, sodium bicarbonate and magnesium stearate were sieved through a 40-mesh screen for later use. 100 g of TBN (API), 100 g of mannitol, 10 g of Polyvidone K30, 25 g of Crospovidone, and 60 g of sodium bicarbonate were weighed, and mixed for 30 min in a hopper mixer in the laboratory. Then, 1 g of magnesium stearate was added and mixed for another 1 min. The resulting material was directly tableted.

[0078] Then the tablet cores were added to a high-efficiency coating machine, and the prepared isolation coating solution containing 8.78 g of hydroxypropyl cellulose, 8.78 g of talc, and 128.77 g of absolute ethanol was added. The weight was increased by 5.93%. Next, a moisture barrier forming solution containing 14.49 g of Opadry, and 76.07 g of pure water was added. The weight was increased by 4.62%. After that, an enteric coating solution containing 28.31 g of hydroxypropyl methylcellulose acetate succinate (HPMCAS, AS-HG), 2.26 g of triethyl citrate, 1.42 g of titania, 5.17 g of talc, 63.34 g of absolute ethanol, and 253.37 of pure water was added, and the enteric layer accounted for 8.63% by weight. Thus, TBN enteric-coated tablets were obtained.

Example 21

[0079] TBN (API), mannitol, Crospovidone, sodium bicarbonate and magnesium stearate were sieved through a 40-mesh screen for later use. 100 g of TBN (API), 100 g of mannitol, 10 g of Polyvidone K30, 25 g of Crospovidone, and 60 g of sodium bicarbonate were weighed, and mixed for 30 min in a hopper mixer in the laboratory. Then, 1 g of magnesium stearate was added and mixed for another 1 min. The resulting material was directly tableted.

[0080] Then the tablet cores were added to a high-efficiency coating machine, and the prepared isolation coating solution containing 8.78 g of hydroxypropyl cellulose, 8.78 g of talc, and 128.77 g of absolute ethanol was added. The weight was increased by 5.93%. Next, a moisture barrier forming solution containing 14.49 g of Opadry, and 76.07 g of pure water was added. The weight was increased by 4.62%. After that, an enteric coating solution containing 27.16 g of hydroxypropyl methylcellulose acetate succinate (HPMCAS, AS-LG), 2.17 g of triethyl citrate, 1.36 g of titania, 4.96 g of talc, 60.17 g of absolute ethanol, and 243.08 g of pure water was added, and the enteric coating accounted for 8.28% by weight. Thus, TBN enteric-coated tablets were obtained.

Example 22

[0081] TBN (API), mannitol, Crospovidone, sodium bicarbonate and magnesium stearate were sieved through a 40-mesh screen for later use. 100 g of TBN (API), 100 g of mannitol, 10 g of Polyvidone K30, 25 g of Crospovidone, and 60 g of sodium bicarbonate were weighed, and mixed for 30 min in a hopper mixer in the laboratory. Then, 1 g of magnesium stearate was added and mixed for another 1 min. The resulting material was directly tableted.

[0082] Then the tablet cores were added to a high-efficiency coating machine, and the prepared isolation coating solution containing 6.61 g of hydroxypropyl cellulose, 6.61 g of talc, and 101.37 g of absolute ethanol was added. The weight was increased by 4.67%. Next, a moisture barrier forming solution containing 15.71 g of Opadry, and 82.47 g of pure water was added. The weight was increased by 5.07%. After that, an enteric coating solution containing 23.70 g of Eudragit L100-55, 2.37 g of triethyl citrate, 2.37 g of titania, 11.85 g of talc, and 354.69 g of 95% ethanol was added, and the enteric layer accounted for 7.28% by weight. Thus, TBN enteric-coated tablets were obtained.

Example 23

[0083] TBN (API), mannitol, Crospovidone, sodium bicarbonate, hydroxypropyl cellulose and magnesium stearate were sieved through a 40-mesh screen for later use. 300 g of TBN (API), 248.4 g of mannitol, 57.6 g of hydroxypropyl cellulose, 51 g of Crospovidone, and 60 g of sodium bicarbonate were weighed, and mixed for 30 min in a hopper mixer in the laboratory. Then, 3 g of magnesium stearate was added, mixed for another 1 min, and directly tableted. Then the tablet cores were added to a high-efficiency coating machine, and the prepared isolation coating solution containing 27.8 g of hydroxypropyl cellulose and 8.2 g of talc was added. The isolation layer accounted for 5% by weight. Next, an enteric coating solution containing 32.3 g of methacrylic acid-ethyl acrylate copolymer, 3.2 g of triethyl citrate, 3.2 g of titania, and 6.5 g of talc was added. The enteric layer accounted for 6% by weight. Thus, TBN enteric-coated tablets were obtained.

Example 24

[0084] TBN (API), mannitol, Crospovidone, sodium bicarbonate, hydroxypropyl cellulose and magnesium stearate were sieved through a 40-mesh screen for later use. 300 g of TBN (API), 248.4 g of mannitol, 57.6 g of hydroxypropyl cellulose, 51 g of Crospovidone, and 60 g of sodium bicarbonate were weighed, mixed for 30 min in a hopper mixer in the laboratory, and granulated in a roller granulator. Then, 3 g of magnesium stearate was added, mixed for another 1 min, and tableted. Then the tablet cores were added to a high-efficiency coating machine, and the prepared isolation coating solution containing 27.8 g of hydroxypropyl cellulose and 8.2 g of talc was added. The isolation layer accounted for 5% by weight. Next, an enteric coating solution containing 32.3 g of methacrylic acid-ethyl acrylate copolymer, 3.2 g of triethyl citrate, 3.2 g of titania, and 6.5 g of talc was added. The enteric layer accounted for 6% by weight. Thus, TBN enteric-coated tablets were obtained.

Example 25

[0085] TBN (API), mannitol, Crospovidone, sodium bicarbonate, hydroxypropyl cellulose and magnesium stearate were sieved through a 40-mesh screen for later use. 300 g of TBN (API), 248.4 g of mannitol, 57.6 g of hydroxypropyl cellulose, 51 g of Crospovidone, and 60 g of sodium bicarbonate were weighed, mixed for 30 min in a hopper mixer in the laboratory, and granulated in a roller granulator. Then, 3 g of magnesium stearate was added, mixed for another 1 min, and tableted. Then the tablet cores were added to a high-efficiency coating machine, and the prepared isolation coating solution containing 27.8 g of hydroxypropyl cellulose and 8.2 g of talc was added. The isolation layer accounted for 5% by weight. Next, an enteric coating solution containing 16.2 g of methacrylic acid-ethyl acrylate copolymer, 1.6 g of triethyl citrate, 1.6 g of titania, and 3.3 g of talc was added. The enteric layer accounted for 3% by weight. Thus, TBN enteric-coated tablets were obtained.

[0086] Performance Tests

[0087] (1) The tablet cores prepared in Example 1 and Example 2 were allowed to store under high humidity and high temperature conditions for 10 days to investigate their stability. For specific experimental procedures, refer to the Technical Guidelines for the Stability of Chemical Drugs. The results are shown in Table 1 below.

TABLE-US-00001 TABLE 1 Stability test results of TBN tablet cores under high temperature and high humidity conditions RRT (%) Total Storage Time 1.21 impurity Prescription conditions (day) (Pyrazine-carbaldehyde) 1.73 1.88 (%) Example 1 Frozen and  0 0.03 0.04 0.03 0.19 sealed 60° C. RH75% 10 0.01 0.04 0.03 0.18 Room 10 0.07 0.04 0.03 0.24 temperature, RH92.5% Example 2 Frozen and  0 0.03 0.04 0.03 0.18 sealed 60° C./RH75% 10 0.01 0.04 0.03 0.20 Room temperature, 10 0.06 0.04 0.03 0.23 RH92.5%

[0088] Note: Only individual impurities of >0.03% are shown in this table.

[0089] The results show that related substances in the examples have no significant increase, and the stability is good.

[0090] (2) The performance indicators of the prepared tablet cores with the compositions of Example 5 and Example 6 were tested. For specific experimental procedures, refer to Guidelines for Pharmaceutical Manufacturing, Chinese Pharmacopeia 2015 Edition. The results are shown in Table 2 below.

TABLE-US-00002 TABLE 2 Main observation indicators and results Observation indicators Example 5 Example 6 Compressibility Good Good Cracking or not No No Fluidity Good Good Hardness 50-60N 60-70N Disintegration time 5-7 min 6-8 min Punch sticking No No Friability 0.61% 0.22%

[0091] The results show that increasing the amount of binder has little effect on the disintegration time.

[0092] (3) The performance indicators of the prepared tablet cores with the compositions of Example 7 and Example 9 were tested. For specific experimental procedures, refer to Guidelines for Pharmaceutical Manufacturing, Chinese Pharmacopeia 2015 Edition. The results are shown in Table 3 below.

TABLE-US-00003 TABLE 3 Hardness and results Name Example 7 Example 9 Hardness (N) 130-150 (main 126-158 (main pressure: 15 KN) pressure: 13-18 KN) Preparation Direct tableting Dry granulation process

[0093] The results show that the composition of the present invention can be prepared by direct tableting, or by dry granulation.

[0094] (4) The disintegration time of the tablet core prepared in Examples 10-12 was determined. For specific experimental procedures, refer to Guidelines for Pharmaceutical Manufacturing, Chinese Pharmacopeia 2015 Edition. The results are shown in Table 4 below.

TABLE-US-00004 TABLE 4 Disintegration time and results Name Example 10 Example 11 Example 12 Disintegration time 15-17 14-17 12-13 (min)

[0095] The results show that all the tablets can meet the requirements of medicinal use.

[0096] (5) The enteric-coated tablets prepared in Example 13 were allowed to store under high humidity and high temperature conditions for 10 days to investigate their stability. The specific test method is the same as that shown in the performance test (1), and the results are shown in Table 5 below.

TABLE-US-00005 TABLE 5 Stability results of TBN tablets under high temperature and high humidity conditions RRT 1.21 Total Storage Time (Pyrazine- impurity Prescription conditions (day) carbaldehyde) 1.71 (%) Example 13 Frozen and 0 0.07 0.00 0.07 sealed 60° C. RH 75% 10 0.37 0.06 0.44

[0097] The results show that the composition of the isolation layer of the present invention can effectively improve the stability of enteric-coated tablets.

[0098] (6) The dissolution rate of the TBN enteric-coated tablets in Examples 15 and 16 were tested. For specific experimental procedures, refer to the “Technical Guidelines for the Dissolution Test of Common Oral Solid Preparations”. The results are shown in Table 6.

TABLE-US-00006 TABLE 6 Dissolution rate test Name Example 15 Example 16 Buffer phase: The dissolution rate Q 100 101 is equal to 70% in 60 minutes.

[0099] The results show that the weight increased by coating the isolation layer has no significant effect on the dissolution rate.

[0100] (7) The TBN enteric-coated tablets in Examples 17 and 18 were allowed to store at 50° C. and RH75% for 60 days and 40° C. and RH75% for 90 days to investigate their stability. The related substances were tested as shown in Table 7.

TABLE-US-00007 TABLE 7 Test data of related substances in TBN enteric-coated tablets RRT Total Storage Time 1.21 impurity Prescription Specification conditions (day) (Pyrazine-carbaldehyde) 1.71 (%) Example 17 100 mg Frozen and  0 0.04 <0.01 0.04 sealed 50° C. 10 0.07 <0.01 0.07 RH75% 20 0.08 <0.01 0.08 30 0.09 <0.01 0.09 60 0.09 <0.01 0.09 40° C. 30 0.06 <0.01 0.06 RH75% 60 0.07 <0.01 0.07 90 0.08 <0.01 0.08 Example 18 300 mg Frozen and  0 0.04 <0.01 0.04 sealed 50° C. 10 0.06 <0.01 0.06 RH75% 20 0.07 <0.01 0.07 30 0.10 <0.01 0.10 60 0.12 <0.01 0.12 40° C. 30 0.04 <0.01 0.04 RH75% 60 0.08 <0.01 0.08 90 0.08 <0.01 0.08

[0101] The results show that both the tablets in Example 17 and Example 18 have good stability.

[0102] (8) The enteric-coated tablets prepared in Examples 19-22 were allowed to store at 50° C. and RH75% for 30 days and 40° C. and RH75% for 90 days to investigate their stability. The test method was the same as the performance test (7). The test results are shown in Table 8.

TABLE-US-00008 TABLE 8 Test data of related substances in TBN enteric-coated tablets RRT Total Storage Time 1.21 impurity Prescription Specification conditions (day) (Pyrazine-carbaldehyde) 1.71 (%) Example 19 100 mg Frozen and  0 0.04 <0.01 0.04 sealed 50° C. 30 0.09 <0.01 0.09 RH75% 40° C. 30 0.06 <0.01 0.06 RH75% 60 0.07 <0.01 0.07 90 0.08 <0.01 0.08 Example 20 100 mg Frozen and  0 0.04 <0.01 0.04 sealed 50° C. 30 0.08 <0.01 0.08 RH75% 40° C. 30 0.06 <0.01 0.06 RH75% 60 0.07 <0.01 0.07 90 0.09 <0.01 0.09 Example 21 100 mg Frozen and  0 0.04 <0.01 0.04 sealed 50° C. 30 0.10 <0.01 0.10 RH75% 40° C. 30 0.06 <0.01 0.06 RH75% 60 0.08 <0.01 0.08 90 0.08 <0.01 0.08 Example 22 100 mg 50° C.  0 0.09 <0.01 0.09 RH75% 30 0.10 <0.01 0.10 40° C. 30 0.07 <0.01 0.07 RH75% 60 0.09 <0.01 0.09 90 0.09 <0.01 0.09

[0103] The results show that the related substances have no obvious changes after storage under the conditions of 40° C. and RH75% for three months and 50° C. and RH75% for 1 month, indicating that TBN has good stability when the above four materials are used as the enteric layer coating material.

[0104] (9) The dissolution rate of TBN enteric-coated tablets prepared according to Example 25 was tested, and the test method was the same as the performance test (6). The results are shown in Table 9.

TABLE-US-00009 TABLE 9 Dissolution rate test Name Example 25 Buffer phase: The dissolution rate 88 Q is equal to 70% in 60 minutes. Process Dry granulation

[0105] The result shows that the dissolution rate meets the requirements.

[0106] (10) Bioavailability test: Pharmacokinetic study of TBN (API) and enteric-coated tablets in beagle dogs

[0107] 6 beagle dogs were randomly divided into 2 groups, each group having 3 animals. Each test animal was given with TBN (API) at a dosage of 175 mg, or 1 enteric-coated tablet with a specification of 175 mg prepared following the method in Example 17 by oral gavage. The blood sample was collected at various times (0.08, 0.25, 0.5, 1, 1.5, 2, 4, 8, 12, and 24 h), and analyzed by LC-MS/MS. A drug concentration-time curve was plotted to calculate the pharmacokinetic parameters.

TABLE-US-00010 TABLE 10 Pharmacokinetic parameters of non-compartmental model after oral administration of enteric-coated tablets in beagle dogs Standard Parameter 101 102 103 Average deviation AUC(0-t) 24338.4 22494.0 18404.9 21745.7 3036.7 (ng/mL*h) AUC (0-∞) 24338.5 22494.2 18404.9 21745.9 3036.7 (ng/mL*h) MRT (0-t) (h) 1.30 1.57 1.62 1.50 0.17 Vz/F (L/kg) 0.57 0.62 0.72 0.64 0.08 CLz/F (L/h/kg) 0.58 0.64 0.83 0.68 0.13 T½z (h) 0.68 0.68 0.60 0.65 0.04 Tmax (h) 0.50 1.00 1.00 0.83 0.29 Cmax (ng/mL) 19688.09 19226.44 11617.97 16844.17 4531.90 Body Weight 12.40 12.23 11.52 12.05 0.47 (kg) Dosing (mg/kg) 14.11 14.31 15.19 14.54 0.57

TABLE-US-00011 TABLE 11 Pharmacokinetic parameters of non-compartmental model after oral administration of TBN (API) in beagle dogs Standard Parameter 201 202 203 Average deviation AUC(0-t) 5290.7 6935.2 16503.2 9576.4 6054.9 (ng/mL*h) AUC (0-∞) 5294.6 6935.3 16503.3 9577.7 6053.5 (ng/mL*h) MRT (0-t) (h) 0.62 0.89 0.98 0.83 0.18 Vz/F (L/kg) 1.39 1.43 0.85 1.22 0.32 CLz/F (L/h/kg) 2.57 2.02 0.84 1.81 0.89 T½z (h) 0.38 0.49 0.71 0.52 0.17 Tmax (h) 0.25 0.25 0.25 0.25 0.00 Cmax (ng/mL) 7280.25 7291.11 15646.14 10072.50 4826.92 Body Weight 12.85 12.52 12.69 12.69 0.17 (kg) Dosing (mg/kg) 13.62 13.98 13.79 13.80 0.18

[0108] The results are shown in Tables 10 and 11 and FIGS. 1 and 2. The data shows that the average C.sub.max of the enteric-coated tablets in the beagle dogs is about 1.67 times the C.sub.max of TBN (API) in the beagle dog, and the bioavailability of the TBN enteric-coated tablets is about 2.3 times that of the TBN (API).

[0109] (11) Pharmacokinetic study of TBN enteric-coated tablets prepared following the method described in Example 25

[0110] 24 beagle dogs (male:female 1:1) were randomly divided into 4 groups (each group having 3 female and 3 male animals). Animals in group A were injected intravenously with a TBN (API) solution at a dosage of 6 mg.Math.kg.sup.−1, and animals in groups B and D were respectively given with TBN enteric-coated tablets at a dosage of 100 and 900 mg.Math.animal.sup.−1 by oral gavage. Blood was taken from the animals in group A before and 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h after administration; and blood was taken from the animals in group B and D before and 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 h after administration. Animals in group C were given TBN enteric-coated tablets at a dosage of 300 mg.Math.animal.sup.−1 for seven consecutive days. Blood was taken from the animals in group C before and 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 h after the first and seventh administration and before and 2 h after the second to sixth administration.

[0111] Detection and analysis by LC-MS/MS were performed and the pharmacokinetic parameters were calculated.

TABLE-US-00012 TABLE 12 Pharmacokinetic parameters in beagle dogs intravenously injected with 6 mg .Math. kg.sup.−1 TBN Param- C.sub.0 MRT.sub.0-inf AUC0.sub.-inf CL VD.sub.SS eter (ng/ml) t.sub.1/2 (h) (h) (ng .Math. h/ml) (ml/kg.Math. min) (L/kg) Mean 12100 0.292 0.298  3560 29.1 0.503  SD  1480 0.138 0.0700  711  6.03 0.0570

TABLE-US-00013 TABLE 13 Pharmacokinetic parameters in Beagle dogs administered with TBN enteric-coated tablets at a dosage of 100, 300 and 900 mg .Math. animal.sup.−1 by oral gavage. t.sub.1/2 T.sub.max C.sub.max AUC.sub.0-t AUC.sub.0-t-dose ng .Math. MRT.sub.0-imf Dose Parameter (h) (h) (ng/ml) (ng .Math. h/ml) kg .Math. (ml .Math. mg).sup.−1 (h) F (%) 100 mg .Math. Mean  0.0804 1.25   4770  5400 424 1.50   71.6 animal.sup.−1 SD NA 0.612  3390  4570 328 NA  55.4 300 mg .Math. Mean 0.673 1.83  15100 24600 634 2.13  107.0 amimal.sup.−1 SD 0.161 0.408  9780 13000 296 0.435  50.2 (first) 900 mg .Math. Mean 0.896 2.50  96000 216000 1890  2.24  319.0 animal.sup.−1 SD 0.105 2.74  45700  83500 697 0.244 118.0 300 mg .Math. Mean 1.08  2.00  22000  38800 NR 1.86  NR animal.sup.−1 SD 0.618 1.10   8760  11200 NR 0.361 NR (seventh)

[0112] After intravenous administration of 6 mg TBN.Math.kg.sup.−1 in beagle dogs, the average terminal elimination half-life (t.sub.1/2) is 0.292 h, the clearance (CL) is 29.1 mL.Math.kg.sup.−1.Math.min.sup.−1, the steady-state apparent volume of distribution (Vdss) is 0.503 L.Math.kg.sup.−1, and the area under the drug concentration-time curve (AUC0-inf) is 3560 ng.Math.h.Math.mL.sup.−1. After the beagle dogs are given TBN enteric-coated tablets at a dosage of 100, 300 and 900 mg.Math.animal.sup.−1 by oral gavage, the average peak time (Tmax) is 1.25, 1.83 and 2.50 h respectively, the peak concentration (Cmax) is 4770, 15100 and 96000 ng.Math.mL.sup.−1 respectively, the AUC.sub.0-t is 5400, 24600 and 216000 ng.Math.h.Math.mL.sup.−1 respectively, the area under the drug concentration per dosage-time curve (AUC.sub.0-t dose) is 424, 634 and 1890 ng.Math.h.Math.kg.Math.(mL.Math.mg).sup.−1 respectively, and the oral bioavailability (F) is 71.6%, 107.0% and 319.0% respectively. These indicate that TBN enteric-coated tablets are absorbed faster in beagle dogs after oral administration and mainly distributed in the extracellular fluid, can be quickly cleared from the body, have a bioavailability increasing with the increase in dose, and have non-linear PK characteristics especially in the high-dose group.

[0113] After a single administration of TBN enteric-coated tablets at a dosage of 100, 300, and 900 mg.Math.animal.sup.−1 to beagle dogs by oral gavage, the dose-related linear increase is basically shown in the dose range of 100-300 mg.Math.animal.sup.−1. In the dose range of 300-900 mg.Math.animal.sup.−1, more than dose-related linear increase is shown. Therefore, more than dose-related linear increase is also shown in the dose range from 100 to 900 mg.Math.animal.sup.−1.

[0114] After the beagle dogs were given TBN enteric-coated tablets at a dosage of 300 mg.Math.animal.sup.−1 by oral gavage for 7 consecutive days, the ratio of AUC.sub.0-t after the 7th administration and the 1st administration is 1.58, and no significant drug accumulation is observation.

[0115] After intravenous administration of TBN, there is no significant difference in exposure levels (C.sub.0, AUC.sub.0-t) between male and female beagle dogs. Except for the low-dose administration by oral gavage, there is no significant difference in the exposure levels (Cmax, AUC.sub.0-t) between male and female beagle dogs after administration of medium and high-dose TBN enteric-coated tablets by oral gavage.