Vonoprazan fumarate tablet and preparation method thereof

Abstract

The invention relates to a fumaric acid Vonoprazan tablet and a preparation method thereof. The tablet core comprises an active component of Vonoprazan fumarate, a filler, a disintegrating agent, an adhesive, a pH regulator and a lubricant. The raw material medicines are suspended in the adhesive and sprayed into the fluidized bed for granulation, so that the loss of small-particle-size raw materials in the granulation process is reduced, the product yield is improved, the product quality is ensured, and the operability of the fluidized bed granulation coating machine is improved. The method is simple in process and suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and specifically relates to a vorapaxar fumarate tablet and a preparation method thereof. Background Art

[0002] Vorapaxar fumarate is a new type of proton pump inhibitor developed by Takeda Pharmaceutical Company of Japan. By competitively blocking the K + -K + -ATPase K + channel, blocking the binding of K + to this enzyme, thereby rapidly inhibiting gastric acid secretion to inhibit acid secretion. Compared with traditional proton pump inhibitors, it has the characteristics of rapid onset, long-lasting effect, and strong stability. Vorapaxar fumarate tablets were first launched in Japan in 2014 and were imported and launched in China in 2019.

[0003] The chemical name of vorapaxar fumarate is 1-[5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine mono-fumarate, and its chemical structural formula is as follows:

[0004]

[0005] Vorapaxar fumarate is slightly soluble in water. In order to achieve rapid release in vitro dissolution, the raw drug needs to be pulverized. After treatment, the particle size of the raw drug is relatively small (D90 is 10-100 μm). When using the traditional fluidized bed one-step granulation process, the raw drug is easily adsorbed on the surface of the equipment, which easily causes losses during the granulation process of small-particle raw materials, and there is a risk of low particle content.

[0006] The present invention aims to solve the problems of low content and instability during the fluidized bed granulation of small-particle raw drugs. By suspending small-particle (D90 is 10-100 μm) raw materials in a binder and spraying them into the fluidized bed for granulation to prepare vorapaxar fumarate tablets, the loss of raw materials during the granulation process can be effectively reduced, and the content of the prepared granules can be ensured to be stable and controllable. Summary of the Invention

[0007] The purpose of the present invention is to overcome the problems existing in the prior art and provide a vorapaxar fumarate tablet and a preparation method thereof, which improve the product quality and are suitable for industrial production.

[0008] The technical solution adopted by the present invention is:

[0009] A vorapaxar fumarate tablet, the tablet core includes an active ingredient vorapaxar fumarate, a filler, a disintegrant, a binder, a pH regulator, and a lubricant.

[0010] Preferably, the filler is selected from lactose, mannitol, starch or microcrystalline cellulose. Further preferably, the filler is a combination of mannitol and microcrystalline cellulose; the disintegrant is selected from sodium carboxymethylcellulose cross-linked, hypromellose phthalate or crospovidone. Further preferably, the disintegrant is sodium carboxymethylcellulose cross-linked; the binder is selected from hydroxypropyl cellulose, hypromellose or polyvinylpyrrolidone. Further preferably, the binder is hydroxypropyl cellulose; the lubricant is selected from magnesium stearate or talc. Further preferably, the lubricant is magnesium stearate; the pH regulator is selected from fumaric acid.

[0011] Preferably, the weight percentage of vonoprazan fumarate in each tablet accounting for the total drug content in the tablet core layer is 10% to 20%, the filler is mannitol and microcrystalline cellulose accounting for 60 to 80% of the total drug content in the tablet core layer, the disintegrant is sodium carboxymethylcellulose cross-linked accounting for 2 to 8% of the total drug content in the tablet core layer, the binder is hydroxypropyl cellulose accounting for 1 to 5% of the total drug content in the tablet core layer, the pH regulator is fumaric acid accounting for 0 to 1% of the total drug content in the tablet core layer, and the lubricant is magnesium stearate accounting for 0 to 3% of the total drug content in the tablet core layer.

[0012] Further preferably, the weight percentage of vonoprazan fumarate in each tablet accounting for the total drug content in the tablet core layer is 12%, the filler is mannitol and microcrystalline cellulose accounting for 79% of the total drug content in the tablet core layer, the disintegrant is sodium carboxymethylcellulose cross-linked accounting for 5% of the total drug content in the tablet core layer, the binder is hydroxypropyl cellulose accounting for 3% of the total drug content in the tablet core layer, and the lubricant is magnesium stearate accounting for 1% of the total drug content in the tablet core layer.

[0013] Preferably, the method for preparing the vonoprazan fumarate tablets comprises the following steps:

[0014] (1) Dissolve hydroxypropyl cellulose, fumaric acid and vonoprazan fumarate in purified water to prepare a drug-containing binder.

[0015] (2) Spray the prepared drug-containing binder into mannitol and microcrystalline cellulose for fluidized bed granulation.

[0016] (3) Screen the granules after fluidized bed granulation and then add sodium carboxymethylcellulose cross-linked and magnesium stearate for total mixing.

[0017] (4) Compress the total mixed granules into plain tablets using special-shaped punches.

[0018] (5) Coat the plain tablets prepared above with a gastric-soluble film coating premix to obtain coated tablets.

[0019] Preferably, the vorinostat fumarate raw material medicine described in step (1) is pulverized by an air jet mill. After pulverization, the particle size D90 of the raw material is 10-100 μm, preferably 11.3 μm.

[0020] The beneficial effects obtained by the present invention are as follows:

[0021] By studying the product prescription and preparation method, the technical problems of raw material loss and yield reduction in the prior art are solved. The method adopted improves the product yield and at the same time improves the product quality, and is suitable for industrial production. Specific embodiments

[0022] The present invention will be further described through the following examples. The examples are only for illustrative purposes and do not limit the scope of the present invention. At the same time, obvious changes and modifications made by those of ordinary skill in the technical field to which the present invention belongs are also included within the scope of the present invention. The technical content not described in detail in the present invention is well-known technology.

[0023] Example 1 (Sample 1)

[0024] A vorinostat fumarate tablet consists of the following raw and auxiliary materials:

[0025] [Table 1] Prescription composition of a film-coated tablet

[0026]

[0027] * The particle size D90 of the vorinostat fumarate raw material medicine is 11.3 μm.

[0028] Preparation method:

[0029] Take about 60 g of vorinostat fumarate raw material medicine, pulverize it with an air jet mill, the pulverization pressure is 0.5 Mpa, and the particle size D90 after pulverization is 11.3 μm.

[0030] (1) Add the pulverized vorinostat fumarate (53.4 g), hydroxypropyl cellulose (13.2), and fumaric acid (0.44 g) to purified water to prepare a drug-containing binder;

[0031] (2) Weigh mannitol (302.5 g) and microcrystalline cellulose (44 g), add them to the fluidized bed and preheat for 5 min, and spray the drug-containing binder for fluidized bed granulation;

[0032] (3) After sizing the particles obtained by fluidized bed granulation, add cross-linked carboxymethyl cellulose sodium and magnesium stearate for total mixing;

[0033] (4) Press the total mixed particles into plain tablets using special-shaped punches;

[0034] (5) Coating the above-prepared plain tablets with a gastric-soluble film coating premix, with a coating weight gain of 4%, to obtain coated tablets with a weight of 229 mg / tablet.

[0035] Example 2 (Sample 2)

[0036] A voruprazan fumarate tablet is composed of the following raw and auxiliary materials:

[0037] [Table 2] Prescription composition of a film-coated tablet

[0038]

[0039] * The particle size D90 of voruprazan fumarate raw material medicine is 20.4 μm.

[0040] Preparation method:

[0041] Take about 60 g of voruprazan fumarate raw material medicine, and pulverize it with an air jet mill. The pulverizing pressure is 0.4 Mpa, and the particle size D90 after pulverization is 20.4 μm.

[0042] (1) Add the pulverized voruprazan fumarate (53.4 g), hydroxypropyl cellulose (13.2), and fumaric acid (0.44 g) to purified water to prepare a medicated binder.

[0043] (2) Weigh mannitol (302.5 g) and microcrystalline cellulose (44 g), add them to the fluidized bed for preheating for 5 min, and spray the medicated binder for fluidized bed granulation.

[0044] (3) Screen the granules after fluidized bed granulation, and then add cross-linked carboxymethyl cellulose sodium and magnesium stearate for total mixing.

[0045] (4) Press the total mixed granules into plain tablets using special-shaped punches.

[0046] (5) Coating the above-prepared plain tablets with a gastric-soluble film coating premix, with a coating weight gain of 4%, to obtain coated tablets with a weight of 229 mg / tablet.

[0047] Example 3 (Sample 3)

[0048] A voruprazan fumarate tablet is composed of the following raw and auxiliary materials:

[0049] [Table 3] Prescription composition of a film-coated tablet

[0050]

[0051] * The particle size D90 of voruprazan fumarate raw material medicine is 55.2 μm.

[0052] Preparation method:

[0053] Take about 120 g of voruprazan fumarate raw material drug, and crush it using an air jet mill. The crushing pressure is 0.3 Mpa, and the particle size D90 after crushing is 55.2 μm.

[0054] (1) Add the crushed voruprazan fumarate (53.4 g), hydroxypropyl cellulose (13.2), and fumaric acid (0.44 g) to purified water to prepare a drug-containing binder.

[0055] (2) Weigh mannitol (302.5 g) and microcrystalline cellulose (44 g), add them to a fluidized bed for preheating for 5 min, and spray the drug-containing binder for fluidized bed granulation.

[0056] (3) Screen the granules after fluidized bed granulation, and then add sodium croscarmellose and magnesium stearate for total mixing.

[0057] (4) Press the total mixed granules into plain tablets using a special-shaped punch die.

[0058] (5) Coating the plain tablets prepared above with a gastric-soluble film coating premix, with a coating weight gain of 4%, to obtain coated tablets with a weight of 229 mg / tablet.

[0059] Example 4 (Sample 4)

[0060] A voruprazan fumarate tablet is composed of the following raw and auxiliary materials:

[0061] [Table 4] Prescription composition of a film-coated tablet

[0062]

[0063] * The particle size D90 of the voruprazan fumarate raw material drug is 70.6 μm.

[0064] Preparation method:

[0065] Take about 60 g of voruprazan fumarate raw material drug, and crush it using an air jet mill. The crushing pressure is 0.2 Mpa, and the particle size D90 after crushing is 70.6 μm.

[0066] (1) Add the crushed voruprazan fumarate (53.4 g), hydroxypropyl cellulose (13.2), and fumaric acid (0.44 g) to purified water to prepare a drug-containing binder.

[0067] (2) Weigh mannitol (302.5 g) and microcrystalline cellulose (44 g), add them to a fluidized bed for preheating for 5 min, and spray the drug-containing binder for fluidized bed granulation.

[0068] (3) Screen the granules after fluidized bed granulation, and then add sodium croscarmellose and magnesium stearate for total mixing.

[0069] (4) Compress the blended granules into plain tablets using a special-shaped punching die;

[0070] (5) Coat the plain tablets prepared above with a gastric-soluble film coating premix, with a coating weight gain of 4%, to obtain coated tablets with a weight of 229 mg / tablet.

[0071] Example 5 (Sample 5)

[0072] A vonoprazan fumarate tablet is composed of the following raw and auxiliary materials:

[0073] [Table 5] Prescription composition of a film-coated tablet

[0074]

[0075] * The particle size D90 of the vonoprazan fumarate raw material medicine is 100.8 μm.

[0076] Preparation method:

[0077] Take about 60 g of vonoprazan fumarate raw material medicine and crush it using an air-flow pulverizer. The crushing pressure is 0.1 Mpa, and the particle size D90 after crushing is 100.8 μm.

[0078] (1) Add the crushed vonoprazan fumarate (53.4 g), hydroxypropyl cellulose (13.2), and fumaric acid (0.44 g) to purified water to prepare a medicated binder;

[0079] (2) Weigh mannitol (302.5 g) and microcrystalline cellulose (44 g) and add them to a fluidized bed for preheating for 5 min, then spray the medicated binder for fluidized bed granulation;

[0080] (3) Screen the granules after fluidized bed granulation and then add croscarmellose sodium and magnesium stearate for blending;

[0081] (4) Compress the blended granules into plain tablets using a special-shaped punching die;

[0082] (5) Coat the plain tablets prepared above with a gastric-soluble film coating premix, with a coating weight gain of 4%, to obtain coated tablets with a weight of 229 mg / tablet.

[0083] Example 6 (Sample 6)

[0084] A vonoprazan fumarate tablet is composed of the following raw and auxiliary materials:

[0085] [Table 6] Prescription composition of a film-coated tablet

[0086]

[0087]

[0088] *The D90 particle size of the voruprazan fumarate raw material drug is 130.5 μm.

[0089] Preparation method:

[0090] Take about 60 g of the voruprazan fumarate raw material drug and crush it with an air jet mill. The crushing pressure is 0.05 Mpa, and the D90 particle size after crushing is 130.5 μm.

[0091] (1) Add the crushed voruprazan fumarate (53.4 g), hydroxypropyl cellulose (13.2), and fumaric acid (0.44 g) to purified water to prepare a drug-containing binder.

[0092] (2) Weigh mannitol (302.5 g) and microcrystalline cellulose (44 g), add them to the fluidized bed for preheating for 5 min, and spray the drug-containing binder for fluidized bed granulation.

[0093] (3) Screen the granules after fluidized bed granulation and then add croscarmellose sodium and magnesium stearate for total mixing.

[0094] (4) Press the total mixed granules into plain tablets using a special-shaped punch die.

[0095] (5) Coat the plain tablets prepared above with a gastric-soluble film coating premix, with a coating weight gain of 4%, to obtain coated tablets with a weight of 229 mg / tablet.

[0096] Comparative Example 1 (Control Sample 1)

[0097] A voruprazan fumarate tablet consists of the following raw and auxiliary materials:

[0098] [Table 7] Prescription composition of a film-coated tablet

[0099]

[0100]

[0101] *The D90 particle size of the voruprazan fumarate raw material drug is 270.0 μm.

[0102] Preparation method:

[0103] (1) Add hydroxypropyl cellulose (13.2) and fumaric acid (0.44 g) to purified water to prepare a binder.

[0104] (2) Weigh mannitol (302.5 g), microcrystalline cellulose (44 g), and untreated voruprazan fumarate raw material drug (53.4 g), add them to the fluidized bed for preheating for 5 min, and spray the binder for fluidized bed granulation.

[0105] (3) Screen the granules after fluidized bed granulation and then add croscarmellose sodium and magnesium stearate for total mixing.

[0106] (4) Compress the blended granules into plain tablets using a special-shaped punch die.

[0107] (5) Coating the plain tablets prepared above with a gastric-soluble film coating premix, with a coating weight gain of 4%, to obtain coated tablets with a weight of 229 mg / tablet.

[0108] Control Example 2 (Control Sample 2)

[0109] A vonoprazan fumarate tablet is composed of the following raw and auxiliary materials:

[0110] [Table 8] Prescription composition of a film-coated tablet

[0111]

[0112] * The particle size D90 of the vonoprazan fumarate raw material drug is 55.2 μm.

[0113] Preparation method:

[0114] (1) Add hydroxypropyl cellulose (13.2) and fumaric acid (0.44 g) to purified water to prepare a binder.

[0115] (2) Weigh mannitol (302.5 g), microcrystalline cellulose (44 g), and the vonoprazan fumarate raw material drug (53.4 g) crushed during the preparation of Example 3 (Sample 3), add them to a fluidized bed for preheating for 5 min, and spray the binder for fluidized bed granulation.

[0116] (3) Screen the granules after fluidized bed granulation and then add croscarmellose sodium and magnesium stearate for blending.

[0117] (4) Compress the blended granules into plain tablets using a special-shaped punch die.

[0118] (5) Coating the plain tablets prepared above with a gastric-soluble film coating premix, with a coating weight gain of 4%, to obtain coated tablets with a weight of 229 mg / tablet.

[0119] The effects of the present invention are demonstrated by the following experiments.

[0120] Experimental Example 1: Investigation of the content of granules after fluidized bed granulation

[0121] (1) Content determination method

[0122] HPLC method

[0123] Flow rate: 1.0 ml / min

[0124] Detection wavelength: 230 nm

[0125] Mobile phase: 0.05 mol / L phosphate buffer - acetonitrile (20:10)

[0126] (2) Results of content determination

[0127] The content results of control samples 1 - 2 and samples 1 - 6 are as follows:

[0128] Table 9 Results of content investigation of particles prepared by fluidized bed

[0129]

[0130] Experimental data show that: when the particle size of the API is small (control sample 2), directly adding the API into the fluidized bed for granulation results in a low particle content, not meeting the quality standard requirements. When the particle size of the API is small and the D90 is 11.3 - 130.5 μm, the API is suspended in the binder, and the particle content of the granules prepared by spraying into the fluidized bed meets the quality standard requirements. This indicates that the method of suspending the API in the binder and spraying it into the fluidized bed for granulation in the present invention can meet the particle content requirements and ensure product quality.

[0131] Experimental example 2: Investigation of crystal form results

[0132] Take the control sample 2 of the present invention (directly adding the API into the fluidized bed for granulation), sample 3 (suspending the raw material in the binder and spraying it into the fluidized bed for granulation) and the used API respectively to detect the crystal form. The experimental results show that: for different addition methods of the API, the crystal form characteristic peaks of the preparation are basically the same, and compared with the crystal form characteristic peaks of the API, the crystal form has not changed.

[0133] Experimental example 3: Dissolution investigation

[0134] Compare the dissolution of samples 1 - 6 prepared in the examples and control sample 1 in pH 6.8 phosphate buffer solution.

[0135] 1. Dissolution method

[0136] Dissolution method: Second method of General Chapter 0931, Volume IV of Chinese Pharmacopoeia 2020 Edition, paddle method

[0137] Dissolution medium: pH 6.8 phosphate buffer solution. 900 ml

[0138] Rotation speed: 30 revolutions per minute

[0139] Temperature: 37 ± 0.5 °C

[0140] Sampling time: 5 min, 10 min, 15 min, 30 min, 45 min, 60 min

[0141] 2. Dissolution results

[0142] Table 10. Dissolution results of samples

[0143]

[0144] The results showed that for Samples 1 to 5, that is, when the D90 of the API particle size was 11.3 to 100.8 μm, the dissolution rate at 15 min was greater than 85%. Combining with the results of the investigation on the content of fluidized bed granulation particles, the preferred range of the D90 of the API particle size of this product was 10 to 100 μm.

Claims

1. A vorinostat fumarate tablet, characterized in that, The tablet core of the tablet comprises vonoprazan fumarate as the active ingredient, a filler, a disintegrant, a binder, a pH regulator, and a lubricant.

2. The vonoprazan fumarate tablet according to claim 1, characterized in that, The filler is selected from lactose, mannitol, starch, or microcrystalline cellulose, preferably a combination of mannitol and microcrystalline cellulose.

3. The vonoprazan fumarate tablet according to claim 1, characterized in that, The disintegrant is selected from sodium carboxymethylcellulose cross-linked, hypromellose phthalate, or crospovidone, preferably sodium carboxymethylcellulose cross-linked.

4. The vonoprazan fumarate tablet according to claim 1, characterized in that, The binder is selected from hydroxypropylcellulose, hypromellose, or polyvinylpyrrolidone, preferably hydroxypropylcellulose.

5. The vonoprazan fumarate tablet according to claim 1, wherein The lubricant is selected from magnesium stearate or talc, preferably magnesium stearate.

6. The vonoprazan fumarate tablet according to claim 1, wherein The pH regulator is selected from fumaric acid.

7. The voriconazole fumarate tablet according to claim 1, wherein The weight percentage of vonoprazan fumarate in each tablet in the total drug content of the tablet core layer is 10% - 20%. The filler, which is mannitol and microcrystalline cellulose, accounts for 60 - 80% of the total drug content of the tablet core layer. The disintegrant, which is sodium carboxymethylcellulose cross-linked, accounts for 2 - 8% of the total drug content of the tablet core layer. The binder, which is hydroxypropylcellulose, accounts for 1 - 5% of the total drug content of the tablet core layer. The pH regulator, which is fumaric acid, accounts for 0 - 1% of the total drug content of the tablet core layer. The lubricant, which is magnesium stearate, accounts for 0.5 - 3% of the total drug content of the tablet core layer.

8. The vonoprazan fumarate tablet according to claim 7, characterized in that, The weight percentage of vonoprazan fumarate in each tablet in the total drug content of the tablet core layer is 12%. The filler, which is mannitol and microcrystalline cellulose, accounts for 79% of the total drug content of the tablet core layer. The disintegrant, which is sodium carboxymethylcellulose cross-linked, accounts for 5% of the total drug content of the tablet core layer. The binder, which is hydroxypropylcellulose, accounts for 3% of the total drug content of the tablet core layer. The lubricant, which is magnesium stearate, accounts for 1% of the total drug content of the tablet core layer.

9. The preparation method of the vonoprazan fumarate tablet according to any one of claims 1 - 7, comprising the following steps: (1) Dissolve hydroxypropylcellulose, fumaric acid, and vonoprazan fumarate in purified water to prepare a medicated binder. (2) Spray the prepared medicated binder into mannitol and microcrystalline cellulose for fluidized bed granulation. (3) Screen the granules after fluidized bed granulation and then add sodium carboxymethylcellulose cross-linked and magnesium stearate for total mixing. (4) Press the total mixed granules into plain tablets using a special-shaped punch die. (5) Coat the plain tablets prepared above with a gastric-soluble film coating premix to obtain coated tablets.

10. The preparation method of the vonoprazan fumarate tablet according to claim 9, characterized in that, In step (1), the vonoprazan fumarate raw material drug is pulverized using an air jet mill, and the particle size D90 of the pulverized raw material is 10 - 100 μm, preferably 11.3 μm.

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