Vonoprasone fumarate taste-masking pellet and preparation method thereof

Abstract

The invention relates to the technical field of pharmacy, and discloses a fumaric acid vonoprasone taste-masking pellet and a preparation method thereof.The fumaric acid vonoprasone taste-masking pellet comprises fumaric acid vonoprasone, a sucrose pellet core, hydroxypropyl methylcellulose and a taste-masking coating material, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose E5, the particle size range of the sucrose pellet core is 0.180 mm-0. 255mm, and the taste-masking coating material is a mixture of the fumaric acid vonoprasone and the sucrose pellet core. A taste-masking coating material is one of Eudragit E100, Eudragit EPO, Eudragit RL 30D and Eudragit NE 30D, the content of the Vonoprazine fumarate accounts for 12%-18% by mass, and the blank pellet core accounts for 70%-80% by mass. According to the Vonoprazan fumarate taste-masking pellet and the preparation method thereof, eudragit is adopted for coating, the udragit is not dissolved in saliva and begins to dissolve when the pH value is smaller than 5.0, the bitter taste of Vonoprazan fumarate can be greatly masked, the compliance of a patient is improved while drug release is not affected, a fluidized bed bottom spraying coating technology is adopted for taste masking, operation is easy, and the preparation method is suitable for industrial production. The taste masking effect is good, and industrial production is easy.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceuticals, and specifically relates to a taste-masked vorapaxar fumarate pellet and a preparation method thereof. Background Art

[0002] Vorapaxar fumarate is a potassium ion-competitive acid blocker (P-CAB), also known as a proton pump inhibitor (hereinafter referred to as: PPI). The marketed dosage form is tablets. This product exerts its effect as a prototype drug without the activation of acid. It mainly competitively and reversibly binds to inhibit K+ and H+ / K+-ATPase, and can stay in gastric parietal cells for a long time, thereby rapidly inhibiting gastric acid secretion.

[0003] However, in the actual operation process, the inventors found that there are still the following problems: There are limitations in the clinical application of vorapaxar fumarate tablets for patients with dysphagia. Developing alternative dosage forms such as dry suspensions and granules is beneficial to solve this difficulty. However, vorapaxar fumarate itself has a strong bitter taste, and common taste-masking techniques such as adding flavoring agents have limited masking effect on the bitter taste of the drug. Therefore, developing a method that can mask the bitter taste of vorapaxar fumarate is of great significance.

[0004] Based on this, the present invention provides a taste-masked vorapaxar fumarate pellet and a preparation method thereof. Summary of the Invention

[0005] Aiming at the deficiencies of the prior art, the present invention provides a taste-masked vorapaxar fumarate pellet and a preparation method thereof, which have the advantages of selecting sucrose pellets as the drug carrier, hypromellose as the drug-carrying film-forming agent, and Eudragit NE 30D as the taste-masking coating material to mask the bitter taste of vorapaxar fumarate, and solves the problems raised in the background art.

[0006] The present invention provides the following technical solutions: A taste-masked vorapaxar fumarate pellet and a preparation method thereof, including vorapaxar fumarate, sucrose pellets, hypromellose, and a taste-masking coating material.

[0007] Preferably, the hypromellose is hypromellose E5.

[0008] Preferably, the particle size range of the sucrose pellets is 0.180 mm to 0.255 mm.

[0009] Preferably, the taste-masking coating material is one of Eudragit E100, Eudragit EPO, Eudragit RL 30D, and Eudragit NE30D.

[0010] Preferably, the content of vonoprazan fumarate is 12% - 18% by mass, the blank pellets are 70% - 80%, the content of hydroxypropyl methylcellulose is 2.5% - 5% by mass, and the content of the taste-masking coating material is 5% - 10% by mass.

[0011] A method for preparing taste-masking pellets of vonoprazan fumarate, comprising the following steps:

[0012] ① Weigh each component according to the designed ratio, prepare an aqueous solution of hydroxypropyl methylcellulose with a concentration of 5% - 8%, and uniformly disperse vonoprazan fumarate in the aqueous solution to obtain the drug-loading layer solution.

[0013] ② Prepare the coating solution from the taste-masking material, with the solid content of the coating solution being 15% - 30%.

[0014] ③ Use the fluidized bed bottom spray coating technology to spray the drug-loading layer solution onto the blank pellets for drug loading to obtain the drug-loaded pellets, with the weight gain of the drug-loading layer being 20% - 25%.

[0015] ④ Use the fluidized bed bottom spray coating technology to spray the coating solution onto the drug-loaded pellets for taste-masking coating to obtain the taste-masking pellets, with the weight gain of the taste-masking layer being 6% - 10%.

[0016] Compared with the prior art, the present invention has the following beneficial effects:

[0017] For the taste-masking pellets of vonoprazan fumarate and its preparation method, the present invention uses Eudragit for coating, which is insoluble in saliva and starts to dissolve when pH < 5.0, can greatly mask the bitterness of vonoprazan fumarate, improve patient compliance without affecting drug release, and uses the fluidized bed bottom spray coating technology for taste masking, with simple operation, good taste-masking effect, and easy industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 It is a schematic diagram of the concentration-time curve (cumulative dissolution amount) of Example 2 of the present invention and vonoprazan fumarate raw material drug in artificial saliva;

[0019] Figure 2 It is a schematic structural diagram of the result (μg / ml) of the concentration-time curve (cumulative dissolution amount) of the sample of the present invention in artificial saliva;

[0020] Figure 3 It is a schematic diagram of the investigation result of the taste test of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0021] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0022] Example 1

[0023] Please refer to Figures 1 - 3 , a taste-masked pellet of vonoprazan fumarate and its preparation method, comprising vonoprazan fumarate, sucrose pellet cores, hypromellose, and a taste-masked coating material.

[0024] Among them; the hypromellose is hypromellose E5.

[0025] Among them; the particle size range of the sucrose pellet cores is 0.180 mm to 0.255 mm.

[0026] Among them; the taste-masked coating material is one of Eudragit E100, Eudragit EPO, Eudragit RL 30D, and Eudragit NE 30D.

[0027] Among them; the mass percentage of vonoprazan fumarate is 12% to 18%, the blank pellet cores are 70% to 80%, the mass percentage of hypromellose is 2.5% to 5%, and the mass percentage of the taste-masked coating material is 5% to 10%.

[0028] Prescription composition (batch: 1000 preparation units, unit: g)

[0029] Vonoprazan fumarate 26.72g Sucrose core 100g Hypromellose E5 5g Purified water 95g Eudragit NE30D 35g

[0030] A preparation method of a taste-masked pellet of vonoprazan fumarate is as follows:

[0031] Weigh each component according to the designed ratio, prepare a 5% aqueous solution of hypromellose, uniformly disperse vonoprazan fumarate in the aqueous solution to obtain an upper drug layer solution; use the fluidized bed bottom spray coating technology for the upper drug layer solution, set the inlet air temperature at 65°C, spray it onto the blank pellet cores for drug loading to obtain drug-loaded pellet cores, and the weight gain range of the upper drug layer is 30% to 32%; use the fluidized bed bottom spray coating technology for Eudragit NE30D, set the inlet air temperature at 35°C, spray it onto the drug-loaded pellet cores for taste-masked coating to obtain taste-masked pellets, and the weight gain range of the taste-masked layer is 8% to 10%.

[0032] Example 2

[0033] Vonoprazan fumarate 26.72g Sucrose core 100g Hypromellose E5 8g Purified water 92g Eudragit NE30D 27g

[0034] The preparation method of the taste-masked pellets of voruprazan fumarate is as follows: Weigh each component according to the designed ratio, prepare an 8% aqueous solution of hypromellose, and uniformly disperse voruprazan fumarate in this aqueous solution to obtain the solution for the upper drug layer; adopt the fluidized bed bottom spray coating technology for the said solution for the upper drug layer, set the inlet air temperature at 65 °C, spray it onto the blank pellets for drug loading to obtain the drug-loaded pellets, and the weight gain range of the upper drug layer is 33% - 35%; adopt the fluidized bed bottom spray coating technology for Eudragit NE30D, set the inlet air temperature at 35 °C, spray it onto the drug-loaded pellets for taste-masking coating to obtain the taste-masked pellets, and the weight gain range of the taste-masking layer is 6% - 8%.

[0035] Example 3

[0036] Vonoprazan fumarate 26.72g Sucrose core 95g Hypromellose E5 6g Purified water 94g Eudragit NE30D 30g

[0037] The preparation method of the taste-masked pellets of voruprazan fumarate is as follows: Weigh each component according to the designed ratio, prepare a 6% aqueous solution of hypromellose, and uniformly disperse voruprazan fumarate in this aqueous solution to obtain the solution for the upper drug layer; adopt the fluidized bed bottom spray coating technology for the said solution for the upper drug layer, set the inlet air temperature at 65 °C, spray it onto the blank pellets for drug loading to obtain the drug-loaded pellets, and the weight gain range of the upper drug layer is 33% - 35%; adopt the fluidized bed bottom spray coating technology for Eudragit NE30D, set the inlet air temperature at 35 °C, spray it onto the drug-loaded pellets for taste-masking coating to obtain the taste-masked pellets, and the weight gain range of the taste-masking layer is 6% - 8%.

[0038] Detect the taste-masking effects of Examples 1 - 3, and investigate the dissolution rate experiments of the taste-masked pellets of Examples 1 - 3 of the present invention and voruprazan fumarate raw material drug in artificial saliva (pH 6.0) within 1 h:

[0039] The determination conditions are as follows:

[0040] Volume of artificial saliva: 250 ml;

[0041] Sample dosage: Taste-masked pellets equivalent to 26.72 mg of voruprazan fumarate, 26.72 mg of voruprazan fumarate

[0042] Determination temperature: 37 °C ± 0.5 °C;

[0043] Shaking mode: Shaking on a shaker, 100 rpm / min, cyclic shaking;

[0044] Sampling time: 5 min, 10 min, 15 min, 30 min, 45 min, 60 min

[0045] Sampling volume: 5 ml, and simultaneously supplement the blank solution with the same volume and the same temperature;

[0046] Detection method: HPLC

[0047] The measured results are as Figure 1 and Figure 2 shown. As Figure 2 shown, in Examples 1, 2, and 3, there was almost no dissolution in artificial saliva for 60 min, while vorinostat fumarate dissolved rapidly in artificial saliva, indicating that the examples in the present invention can significantly control the dissolution of vorinostat fumarate in saliva, thereby masking the generation of bitterness.

[0048] To evaluate the taste-masking effect of Examples 1-3 of the present invention, a taste test of Examples 1-3 of the present invention and vorinostat fumarate raw material drug was conducted:

[0049] Experimental method: The taste-masked pellets prepared in Examples 1-3 of the present invention were respectively added to drinking water to prepare taste samples containing 1 mg / ml of vorinostat. At the same time, a vorinostat fumarate raw material drug solution containing 1 mg / ml of vorinostat was used as a control solution. Ten healthy subjects aged 18-26 years (male-female ratio 1:1) were selected. Before tasting, they rinsed their mouths 5 times with drinking water from the same source. They tasted the taste samples of Examples 1-3 and the standard bitter solution respectively, and recorded the bitterness grades of each sample. Before tasting each sample, they needed to rinse their mouths 5 times. The bitterness grades ranged from none to bitter, namely no bitterness, slightly bitter, somewhat bitter, bitter, relatively bitter, and extremely bitter. The results of the taste test are referred to Figure 3 According to Figure 3 it was known that after the healthy subjects tasted the samples of Examples 1-3 and compared them with the control solution, the bitterness of Examples 1-3 was between no bitterness and slightly bitter, indicating that the examples in the present invention can significantly mask the bitterness of vorinostat fumarate.

[0050] It should be noted that in this article, relational terms such as first and second are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the term "comprising", "including" or any other variant thereof is intended to cover non-exclusive inclusion, so that a process, method, article or device comprising a series of elements not only includes those elements, but also includes other elements not expressly listed, or elements inherent to such process, method, article or device.

[0051] Although the embodiments of the present invention have been shown and described, for those of ordinary skill in the art, it can be understood that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the present invention. The scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A taste-masked pellet of vonoprazan fumarate, characterized in that: The invention comprises vonoprazan fumarate, a sucrose pellet core, hypromellose and a taste-masking coating material.

2. The vonoprazan fumarate taste-masked pellets and preparation method thereof according to claim 1, characterized in that: The hypromellose is hypromellose E5.

3. The vonoprazan fumarate taste-masked pellets and preparation method thereof according to claim 1, characterized in that: The particle size of the sucrose pellet core is in the range of 0.180 mm to 0.255 mm.

4. The vonoprazan fumarate taste-masked pellets and preparation method thereof according to claim 1, characterized in that: The taste-masking coating material is one of Eudragit E100, Eudragit EPO, Eudragit RL 30D, and Eudragit NE 30D.

5. The vonoprazan fumarate taste-masked pellets and preparation method thereof according to claim 1, characterized in that: The mass percentage of the vonoprazan fumarate is 12% to 18%, the mass percentage of the blank pill core is 70% to 80%, the mass percentage of the hypromellose is 2.5% to 5%, and the mass percentage of the taste-masking coating material is 5% to 10%.

6. A method for preparing vonoprazan fumarate taste-masked pellets according to claims 1-5, comprising the following steps: ① Weigh each component according to the designed ratio, prepare the hydroxypropyl methylcellulose into an aqueous solution with a concentration of 5% to 8%, and evenly disperse vonoprazan fumarate in the aqueous solution to obtain an upper drug layer solution; ② The taste masking material is prepared into a coating liquid, wherein the solid content of the coating liquid is 15% to 30%; ③ The drug layer solution is sprayed onto the blank pill cores by fluidized bed bottom spray coating technology to obtain drug-coated pill cores, and the weight of the drug layer increases by 20% to 25%; ④ The coating liquid is sprayed onto the upper pill core by fluidized bed bottom spray coating technology to perform taste-masking coating to obtain taste-masked micropellets, and the taste-masking layer increases in weight by 6% to 10%.

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