Vonoprazan-containing pharmaceutical composition as well as preparation method and application of Vonoprazan-containing pharmaceutical composition

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a pharmaceutical composition containing Vonoprazan as well as a preparation method and application of the pharmaceutical composition. The composition contains the 15-hydroxystearic acid polyethylene glycol ester and the polycarbophil, so that the stability of the fumarate vonorbitan tablet in the preparation and storage processes is effectively ensured; through investigation under the conditions of high temperature, illumination and acceleration, the product has good stability, especially the drug does not contain N-nitrosovonoprazan, and the safety of the fumaric acid vonoprazan tablet is improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a pharmaceutical composition containing vonoprazan, its preparation method, and its uses. Background Technology

[0002] Vonorazan fumarate, chemically named 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrolo-3-yl]-N-methylmethylamine fumarate monosalt, has the molecular formula: C 21 H 20 FN3O6S, molecular weight: 461.46, structural formula as follows: .

[0003] Vonoprazan fumarate, marketed in China in December 2019 under the brand name "Walker," is the first potassium-competitive acid blocker approved for the Chinese market. It provides a new treatment option for reflux esophagitis and will significantly improve the quality of life for patients with reflux esophagitis.

[0004] According to the instructions, the original formulation composition contains D-mannitol, microcrystalline cellulose, croscarmellose sodium cellulose, hydroxypropyl cellulose, fumaric acid, magnesium stearate, hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide, yellow iron oxide, and red iron oxide.

[0005] Vonoprazan fumarate has poor solubility in water, being only slightly soluble. To improve the dissolution and bioavailability of the formulation, the raw material must be pulverized before use. However, the pulverized raw material has a significant electrostatic effect, exhibiting aggregation, adsorption, and high surface energy, resulting in low dissolution and incomplete dissolution of the formulation product. The process is also difficult to operate, the active ingredients are easily lost, and the tablet content uniformity is poor.

[0006] CN201910919215.6 discloses a highly stable, rapidly releasing solid dosage form and its preparation method. The solid dosage form is prepared from the following raw materials: a co-pulverized powder containing vonoprazan fumarate as the active ingredient and an organic acid, and an excipient. However, the co-pulverized powder proposed in this patent has a low yield in actual operation, exhibits significant static electricity, and suffers from poor powder flowability, which is detrimental to the product preparation process. Furthermore, the direct-compression powder process has high requirements for material flowability, making it unsuitable for large-scale production.

[0007] CN202010392916.1 discloses a solid dosage form with high bioavailability. The active pharmaceutical ingredient is mixed with a sucrose fatty acid ester, micronized, and then an excipient is added to prepare the solid dosage form. In this invention, the active pharmaceutical ingredient is mixed with the sucrose fatty acid ester and then micronized. This process ensures close contact between the sucrose fatty acid ester and the active ingredient, resulting in excellent adsorption of the active ingredient onto the sucrose fatty acid ester. The lipophilic groups in the fatty acids can quickly permeate the body's biological membranes, improving the membrane permeability of the active pharmaceutical ingredient, enhancing the intestinal wall permeability of the formulation, and significantly improving the bioavailability of the formulation.

[0008] CN202010646981.2 provides a tablet containing vonoprazan fumarate, which is made from the following components in parts by weight: 10-15 parts vonoprazan fumarate, 65-75 parts mannitol, 2-5 parts organic acid, 2-4 parts hydroxypropyl cellulose, 8-12 parts microcrystalline cellulose, 2-6 parts croscarmellose sodium, 0.5-2 parts magnesium stearate, 3-4 parts coating powder, and 0.2-1.0 parts polyethylene glycol. The tablets prepared using the method of this invention avoid the wet-heat process; they have good particle flowability and compressibility, do not stick to the punch, have a smooth surface, meet the acceptable friability requirements, and have stable tablet weight. The particle size d90 of the pulverized active component vonoprazan fumarate is 18-85 μm.

[0009] CN202110463116.9 relates to a tablet containing vonoprazan fumarate and its preparation method. The tablet or its core comprises the active ingredient vonoprazan fumarate, internal excipients, and external excipients. In its preparation process, the active ingredient is first dissolved with one or more internal excipients, and then granulated in a fluidized bed with added filler in one step. The resulting dry granules are pulverized through an 18-40 mesh sieve and then mixed with external excipients for tableting. The internal excipients are fillers, stabilizers, and binders; the external excipients are disintegrants and lubricants. This invention significantly solves the problem of content loss due to electrostatic charge and adsorption after pulverization of small-sized formulation raw materials through a simple one-step fluidized bed granulation, and also solves the problems of easy sticking and difficulty in tableting, significantly improving dissolution rate and bioavailability.

[0010] CN202211195597.0 provides a gastric retention tablet containing vonoprazan fumarate, comprising the active ingredient vonoprazan fumarate, hydroxypropyl methylcellulose, sodium bicarbonate, polyethylene glycol, carnauba wax, mannitol, and magnesium stearate. The particle size d90 of the pulverized active ingredient vonoprazan fumarate is <200 μm.

[0011] CN202410916545.0 relates to a vonoprazan fumarate tablet, its preparation method, and its use. The tablet comprises a tablet core and a coating covering the outer surface of the tablet core. Based on the total weight of the tablet core, the raw materials of the tablet core include: 5.0–20.0 wt% vonoprazan fumarate, 65.5–90.0 wt% filler, 0.05–1.0 wt% acidic excipients, 2.0–8.0 wt% disintegrant, 0.5–2.5 wt% lubricant, and 0.5–3.0 wt% binder. The particle size of the vonoprazan fumarate satisfies any value of D90 between 23 and 136 μm, any value of D50 between 10 and 48 μm, and any value of D10 between 6 and 27 μm.

[0012] The original patent CN102743330B provides a solid formulation with improved stability during light exposure, comprising titanium dioxide, a plasticizer, and a chain organic acid. Due to the presence of a secondary amine structure in the compound, it is prone to generating nitrosamine impurities with residual nitrites in the excipients. N-Nitroso Vonoprazan (CAS: 2932441-73-9) has the following structural formula: .

[0013] To improve the stability of vonoprazan fumarate tablets, organic acids need to be added. However, acidic conditions promote the formation of nitrosamine impurities, posing a challenge to their resolution. In August 2022, Phahhom Pharmaceuticals announced the detection of trace amounts of the nitrosamine impurity N-Nitroso vonoprazan in commercial batches of Voquezna, directly causing Voquezna to fail to launch on time.

[0014] KR20250085616A uses wet granulation and an ethanol solution containing a pH adjuster as a binder to inhibit the production of N-nitrosoponopranin in the drug.

[0015] WO2025064381A1 provides a method for preparing a vonoprazan pharmaceutical formulation using ascorbic acid, wherein the vonoprazan pharmaceutical formulation has a reduced level of nitrosamine drug substance-associated hetero-N-nitrosoprazan (NDSRI). The formulation prepared therefrom is also described. In one aspect, the method uses ascorbic acid in a wet granulation step, which, under processing conditions, is expected to promote the instability and degradation of ascorbic acid, but successfully reduces the NDSRI. In another aspect, a method is provided for preparing a rapidly dissolving oral dosage form of vonoprazan with a reduced NDSRI level, such as a rapidly dissolving tablet or an orally disintegrating tablet.

[0016] Currently, based on relevant patents and literature regarding vonoprazan fumarate formulations, the main problems with these formulations include: 1. Tablet stability: photodegradation of tablets and the formation of nitrosamine impurities such as N-nitroso vonoprazan; tablet disintegration or dissolution problems; 2. The preparation process is complex and unstable, resulting in significant differences in tablet composition. Summary of the Invention

[0017] In view of the problems existing in the prior art, the present invention provides a vonoprazan fumarate pharmaceutical composition and its preparation method. This composition improves the dissolution rate of vonoprazan fumarate, avoids the active ingredient pulverization process, and reduces the impurity content of the formulation, thus improving stability. It also has advantages such as rapid disintegration, small tablet weight variation, and uniform content. The formulation disclosed in this invention has the advantages of simple preparation method and high bioavailability, making it suitable for industrial production.

[0018] Specifically, the present invention is achieved through the following technical solution: A vonoprazan fumarate pharmaceutical composition comprising vonoprazan fumarate, polyethylene glycol 15-hydroxystearate, polycarboxyphene, and other pharmaceutically acceptable fillers, disintegrants, and lubricants.

[0019] Preferably, in the vonoprazan fumarate pharmaceutical composition, the mass ratio of vonoprazan fumarate, polyethylene glycol 15-hydroxystearate, polycarboxyphene, filler, disintegrant, and lubricant per unit dosage form is 1:0.1-0.5:0.1-0.5:4-22:0.3-1:0.05-0.5, wherein the active ingredient vonoprazan fumarate is vonoprazan (C 17 H 16 (FN3O2S) calculation.

[0020] Preferably, the filler is one or more of mannitol, microcrystalline cellulose, lactose, pregelatinized starch, and starch. Mannitol and microcrystalline cellulose are further preferred.

[0021] Preferably, the disintegrant is selected from one or a mixture of two or more of croscarmellose sodium, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, croscarmellose, and starch. Croscarmellose sodium is more preferred.

[0022] Preferably, the lubricant is one or more of magnesium stearate, calcium stearate, talc, and sodium stearate fumarate. Magnesium stearate is further preferred.

[0023] The vonoprazan fumarate pharmaceutical composition is preferably a solid dosage form, such as tablets, granules, powders, sustained-release tablets, or pellets; more preferably, the solid dosage form of the vonoprazan fumarate pharmaceutical composition of the present invention is a tablet.

[0024] The present invention also provides a method for preparing tablets of the aforementioned pharmaceutical composition, comprising the following steps: The prescribed amounts of vonoprazan fumarate, polyethylene glycol 15-hydroxystearate, and polycarboxyphene are added to a fluidized bed for melt granulation. After the granulation agent is added, filler and disintegrant are added immediately to continue granulation and granulation. Finally, lubricant is added and mixed thoroughly before tableting.

[0025] Preferably, the method for preparing the pharmaceutical composition tablet includes the following steps: Add the prescribed amounts of vonoprazan fumarate, polyethylene glycol 15-hydroxystearate, and polycarboxyphene to a fluidized bed, set the temperature to 30-35℃, and perform melt granulation in the fluidized bed. After melt granulation for 3-5 minutes, immediately add the filler and disintegrant to continue granulation and granulation. Finally, add the lubricant, mix thoroughly and evenly, and then compress into tablets to obtain the final product.

[0026] In a preferred embodiment, the vonoprazan fumarate pharmaceutical composition, per unit dosage form, contains the following component: vonoprazan fumarate (in C... 17 H 16 10 mg of FN3O2S, 2.5 mg of 15-hydroxystearic acid polyethylene glycol ester, 2.5 mg of polycarboxyphene, 115 mg of mannitol, 15 mg of microcrystalline cellulose, 6.5 mg of croscarmellose sodium cellulose and 2.5 mg of magnesium stearate.

[0027] This invention provides a vonoprazan fumarate pharmaceutical composition. Compared with the prior art, this invention overcomes the stability problems of vonoprazan fumarate tablets during preparation and storage. Through testing under high temperature, light, and accelerated conditions, the product has good stability. In particular, the drug does not contain N-nitrosovonoprazan, which improves the safety of vonoprazan fumarate tablets. Detailed Implementation

[0028] The beneficial effects of the present invention will be further described below through embodiments. It should be understood that the following embodiments are for illustrative purposes only and are not intended to limit the scope of protection of the present invention. At the same time, obvious changes and modifications made by those skilled in the art according to the present invention are also included within the scope of protection of the present invention.

[0029] Example 1 Unit dosage form prescription: Preparation process: The prescribed amounts of vonoprazan fumarate, polyethylene glycol 15-hydroxystearate, and polycarboxyphene were added to a fluidized bed. The temperature was set to 30°C, and melt granulation was carried out in the fluidized bed. After granulation for 4 minutes, mannitol, microcrystalline cellulose, and croscarmellose sodium were immediately added, and granulation was continued. Finally, lubricant was added and mixed thoroughly before tableting.

[0030] Example 2 Unit dosage form prescription: Preparation process: Same as in Example 1 Example 3 Unit dosage form prescription: Preparation process: Same as in Example 1 Example 4 Unit dosage form prescription: Preparation process: Same as in Example 1 Example 5 Unit dosage form prescription: Preparation process: Same as in Example 1 Example 6 Unit dosage form prescription: Preparation process: Same as in Example 1 Example 7 Unit dosage form prescription: Preparation process: Same as in Example 1 Example 8 Unit dosage form prescription: Preparation process: Same as in Example 1 Comparative Example 1 Unit dosage form prescription: Preparation process: Same as in Example 1 Comparative Example 2 Unit dosage form prescription: Preparation process: (1) Weigh out the prescribed amounts of vonoprazan fumarate, mannitol, microcrystalline cellulose, and croscarmellose sodium, mix them evenly, and granulate them using a polycarboxymethyl cellulose aqueous solution.

[0031] (2) Place the granulated particles in a fluidized bed for drying.

[0032] (3) After adding magnesium stearate and mixing thoroughly, compress the mixture into tablets.

[0033] Verification Implementation Examples Dissolution test Dissolution curve determination and evaluation of vonoprazan fumarate tablets: Dissolution and release determination method according to the 2020 edition of the Chinese Pharmacopoeia (Part IV, General Chapter 0931), using the second method (paddle method) apparatus. Dissolution media were prepared in pH 1.2 hydrochloric acid solution, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer, with a volume of 900 mL and a rotation speed of 50 rpm. Samples (5 mL) were taken sequentially at 5, 10, 15, and 30 min, filtered through a 0.45 μm filter membrane, and the filtrate was used as the test solution. Simultaneously, dissolution media of the same temperature and volume were added. Weigh approximately 30 mg of vonoprazan fumarate reference standard accurately and place it in a 20 mL volumetric flask. Dissolve and dilute to the mark using sonication with solvent [acetonitrile-0.1 mol / L hydrochloric acid solution (30:70)]. Shake well. Accurately measure an appropriate amount and dilute with dissolution medium to prepare a solution containing approximately 11 μg (10 mg specification) or 22 μg (20 mg specification) of vonoprazan per mL. This solution serves as the reference standard solution. Accurately inject 20 µL each of the reference standard solution and the test solution into the liquid chromatograph and record the chromatograms. Chromatographic conditions: HPLC, C18 (4.6 mm × 25 cm, particle size 5 μm), detection wavelength 230 nm, column temperature 25 °C, flow rate 1 mL / min, injection volume 50 μL. Mobile phase: 0.05 M sodium phosphate buffer (pH 6.8) / acetonitrile / methanol (17:7:6). The amount of dissolution per tablet is calculated using the Vonolasen peak area according to the external standard method.

[0034] Table 1-1 Dissolution Results Table 1-2 Dissolution Results Table 1-3 Dissolution Results Stability test 1. Photostability test: The stability of each sample was measured after 30 days of storage under light (4500 lux ± 500 lux).

[0035] 2. Accelerated stability study: Stability of different sample wafers was studied after being placed at 40℃ and 75%RH for 6 months.

[0036] 2) Methods for determining related substances The high-performance liquid chromatography (HPLC) method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512) was used. Octadecylsilane-bonded silica gel was used as the packing material (column: CAPCELL PAK C18 MGII, 3μm, 4.6mm × 150mm). Mobile phase A consisted of 0.05mol / L potassium dihydrogen phosphate solution (containing 0.3% triethylamine, pH adjusted to 6.2 with phosphoric acid) - acetonitrile - isopropanol (90:5:5), and mobile phase B consisted of 0.04mol / L potassium dihydrogen phosphate solution (containing 0.2% triethylamine, pH adjusted to 6.2 with phosphoric acid or potassium hydroxide solution) - acetonitrile (40:60). Linear gradient elution was performed according to the table below. The flow rate was 1.0 ml / min; the detection wavelength was 220 nm; and the column temperature was 40℃.

[0037] The N-nitrosovonolacron structure is as follows: Table 2-1 Results after the investigation Table 2-2 Results after the investigation Table 2-3 Results after the investigation This invention utilizes polyethylene glycol 15-hydroxystearic acid (PEG) to enhance the dissolution of vonoprazan fumarate, while the addition of polycarboxyphene effectively inhibits its degradation. The combined application of these two substances further prevents the formation of N-nitrosovonoprazan impurities. The combined use of PEG 15-hydroxystearic acid and polycarboxyphene effectively improves product stability.

Claims

1. A vonoprazan fumarate pharmaceutical composition, characterized in that, The composition contains vonoprazan fumarate, polyethylene glycol 15-hydroxystearate, polycarboxyphene, and other pharmaceutically acceptable fillers, disintegrants, and lubricants.

2. The vonoprazan fumarate pharmaceutical composition according to claim 1, characterized in that, The mass ratio of vonoprazan fumarate, polyethylene glycol 15-hydroxystearate, polycarboxyphene, filler, disintegrant, and lubricant in each unit of the pharmaceutical composition is 1:0.1–0.5:0.1–0.5:4–22:0.3–1:0.05–0.

5. Vonoprazan fumarate is the active ingredient vonoprazan (C... 17 H 16 (FN3O2S) calculation.

3. The vonoprazan fumarate pharmaceutical composition according to claim 1, characterized in that, The filler is one or more of mannitol, microcrystalline cellulose, lactose, pregelatinized starch, and starch; mannitol and microcrystalline cellulose are preferred.

4. The vonoprazan fumarate pharmaceutical composition according to claim 1, characterized in that, The disintegrant is selected from one or a mixture of two or more of the following: sodium croscarmellose, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, croscarmellose, and starch; preferably sodium croscarmellose.

5. The vonoprazan fumarate pharmaceutical composition according to claim 1, characterized in that, The lubricant is one or more of magnesium stearate, calcium stearate, talc, and sodium stearate fumarate.

6. The vonoprazan fumarate pharmaceutical composition according to claim 1, characterized in that, The vonoprazan fumarate pharmaceutical composition, in each unit dosage form, contains the following components: 10 mg vonoprazan fumarate, 2.5 mg polyethylene glycol 15-hydroxystearate, 2.5 mg polycarboxyphene, 115 mg mannitol, 15 mg microcrystalline cellulose, 6.5 mg croscarmellose sodium, and 2.5 mg magnesium stearate. The active ingredient vonoprazan fumarate is vonoprazan (C... 17 H 16 (FN3O2S) calculation.

7. The vonoprazan fumarate pharmaceutical composition according to claim 1, characterized in that, The composition is a solid dosage form, one of tablets, granules, powders, sustained-release agents, or pellets.

8. A method for preparing a tablet of a vonoprazan fumarate pharmaceutical composition according to any one of 1-7, characterized in that, Includes the following steps: The prescribed amounts of vonoprazan fumarate, polyethylene glycol 15-hydroxystearate, and polycarboxyphene are added to a fluidized bed for melt granulation. After the granulation agent is added, filler and disintegrant are added immediately to continue granulation and granulation. Finally, lubricant is added and mixed thoroughly before tableting.

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