Vonoprazan fumarate dry suspension and preparation method thereof

Abstract

The present invention relates to the technical field of pharmaceutical preparations, and in particular to a vonoprazan fumarate dry suspension and a preparation method thereof. The vonoprazan fumarate dry suspension comprises a vonoprazan fumarate solid dispersion and an auxiliary material; the vonoprazan fumarate solid dispersion is prepared by a hot melt granulation method from vonoprazan fumarate and a carrier material; the carrier material is selected from one or both of hydroxypropylcellulose and copovidone. The present invention can control vonoprazan fumarate to maintain a good dissolution rate under a dissolution medium simulating in vivo drug release for 120 minutes, and can also control vonoprazan fumarate to maintain less release in an artificial saliva medium for 2 minutes, thereby ensuring that the vonoprazan fumarate dry suspension has a relatively small bitter taste during administration, and successfully prepares vonoprazan fumarate, which has a strong bitter taste, into a dry suspension with good patient compliance.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to vonoprazan fumarate dry suspension and its preparation method. Background Art

[0002] Acid-suppressing drugs are fundamental to the treatment of acid-related diseases, playing a crucial role in promoting mucosal healing and symptom improvement. From H2 receptor antagonists (H2RAs, tidine derivatives) that emerged in the 1970s, to proton pump inhibitors (PPIs, proton pump inhibitors, prazole derivatives) in the 1980s, and then to the potassium-competitive acid blocker (P-CAB) vonoprazan, which was launched in 2015, acid-suppressing drugs have gone through three distinct eras. In the "2020 Chinese Expert Consensus on Gastroesophageal Reflux Disease," the experts stated that PPIs or P-CABs are the first-line drugs for treating gastroesophageal reflux disease.

[0003] Vonoprazan fumarate, chemically named 1-[5-(2-fluorophenyl)-1-(pyridin-3-sulfonyl)-1H-pyrrolo-3-yl]-N-methylmethylamine monofumarate, has the following structural formula:

[0004]

[0005] Vonoprazan fumarate is a novel potassium-competitive acid blocker (P-CAB) developed by Takeda Pharmaceutical Company of Japan. It was first launched in Japan on December 26, 2014. Its marketed dosage form is a film-coated tablet. Vonoprazan fumarate is a lipophilic weak base with a faster onset of action, longer duration of action, and less tendency to cause nocturnal acid breakthrough. As a reversible proton pump inhibitor that competes with potassium ions, it inhibits the binding of K+ to H+-K+-ATPase (proton pump), allowing it to remain in the gastric parietal cells for an extended period, thereby inhibiting gastric acid production and effectively suppressing the formation of upper gastrointestinal mucosal damage. Clinically, it has shown good efficacy and high tolerability and safety in treating acid-related diseases such as erosive esophagitis, Helicobacter pylori infection, duodenal ulcers, and gastric ulcers.

[0006] Vonoprazan fumarate has a strong bitter taste, and when in tablet form, coating effectively masks this taste. The original vonoprazan fumarate tablets marketed in China are 20mg in strength, designed with functional scoring, and the starting dose is half a tablet (10mg), requiring breaking the tablet. Firstly, breaking the tablet results in inaccurate dosage; secondly, breaking the tablet destroys the masking effect of the coating; and thirdly, it leads to poor medication adherence in elderly patients and children with swallowing difficulties.

[0007] Dry suspensions are liquid preparations in which drugs and suitable excipients are formulated into powder or granules, which can be dispersed into a suspension by adding water and shaking before oral administration. However, dry suspensions exhibit limitations when the drug is extremely bitter. Summary of the Invention

[0008] Based on this, the present invention provides a fumarate vonoprazan dry suspension and its preparation method.

[0009] The first aspect of this invention provides a vonoprazan fumarate dry suspension. Its technical solution is as follows:

[0010] A vonoprazan fumarate dry suspension comprises a vonoprazan fumarate solid dispersion and excipients;

[0011] The vonoprazan fumarate solid dispersion is prepared by hot melt granulation of vonoprazan fumarate and a carrier material.

[0012] The carrier material is selected from one or both of hydroxypropyl cellulose and copovidone.

[0013] A second aspect of this invention provides a method for preparing the above-mentioned vonoprazan fumarate dry suspension. The technical solution is as follows:

[0014] A method for preparing a vonoprazan fumarate dry suspension includes the following steps:

[0015] Vonoprazan fumarate and the carrier material were used to prepare a solid dispersion of vonoprazan fumarate by hot melt granulation.

[0016] Vonoprazan fumarate solid dispersion and excipients are mixed to prepare a dry suspension of vonoprazan fumarate.

[0017] Compared with traditional solutions, the present invention has the following advantages:

[0018] To address the inherently bitter taste of vonoprazan fumarate, this invention selected a suitable carrier material and prepared a vonoprazan fumarate solid dispersion using a hot-melt granulation method. The vonoprazan fumarate dry suspension containing this solid dispersion effectively controls both the dissolution rate of vonoprazan fumarate in a simulated in vivo drug release medium (120 min) and the release of vonoprazan fumarate in an artificial saliva medium (2 min), ensuring a minimally bitter taste during administration. This successfully transforms the inherently bitter vonoprazan fumarate into a dry suspension with good patient compliance. Furthermore, the vonoprazan fumarate dry suspension of this invention exhibits excellent suspension homogeneity after adding water, with no precipitation or stratification issues. It is also packaged in unit doses, ensuring accurate dosage and convenient administration. Attached Figure Description

[0019] In order to more clearly illustrate the technical solutions in the embodiments of the present application and to more fully understand the present application and its beneficial effects, the following is a brief introduction to the drawings required for describing the embodiments. Obviously, the drawings described below are only some embodiments of the present application. Those skilled in the art can also derive other drawings based on these drawings without inventive effort.

[0020] Figure 1 Dissolution curves of each embodiment and comparative example in the dissolution medium;

[0021] Figure 2 Release curves for each embodiment and comparative example in artificial saliva medium. Detailed Implementation

[0022] The present invention will be further described in detail below with reference to specific embodiments. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a thorough and complete understanding of the disclosure of the present invention.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0024] the term

[0025] Unless otherwise specified or incompatible herewith, the terms and phrases used herein shall have the following meanings:

[0026] In this invention, the selection range of "and / or", "or / and", and "and / or" includes any one of two or more related listed items, as well as any and all combinations of the related listed items. These arbitrary and all combinations include any two related listed items, any more related listed items, or a combination of all related listed items. It should be noted that when at least three items are connected using at least two conjunctions selected from "and / or", "or / and", and "and / or", it should be understood that the technical solution undoubtedly includes technical solutions connected by "logical AND", and also undoubtedly includes technical solutions connected by "logical OR". For example, "A and / or B" includes three parallel solutions: A, B, and A+B. For example, the technical solution of "A, and / or, B, and / or, C, and / or, D" includes any one of A, B, C, and D (that is, a technical solution that is connected by "logical OR"), as well as any and all combinations of A, B, C, and D, that is, combinations of any two or three of A, B, C, and D, and also combinations of all four of A, B, C, and D (that is, a technical solution that is connected by "logical AND").

[0027] In this invention, terms such as "multiple", "various", "multiple times", and "multi-dimensional" are used, unless otherwise specified, to refer to a quantity greater than or equal to 2. For example, "one or more" means one or more types.

[0028] In this invention, terms such as "preferred," "better," "more suitable," and "ideal" are used only to describe implementation methods or embodiments with better effects, and should be understood not to limit the scope of protection of this invention.

[0029] In this invention, terms such as "further," "even more," and "particularly" are used for descriptive purposes to indicate differences in content, but should not be construed as limiting the scope of protection of this invention.

[0030] In this invention, the terms "optionally," "optionally," and "optional" refer to options that are optional, meaning they are selected from either "with" or "without." If multiple "optional" options appear in a technical solution, unless otherwise specified and there are no contradictions or mutual constraints, each "optional" option is independent.

[0031] In this invention, the terms "first aspect," "second aspect," "third aspect," and "fourth aspect," etc., are used for descriptive purposes only and should not be construed as indicating or implying relative importance or quantity, nor should they be construed as implicitly indicating the importance or quantity of the indicated technical features. Moreover, "first," "second," "third," and "fourth," etc., serve only as a non-exhaustive enumeration and should be understood not to constitute a closed limitation on quantity.

[0032] In this invention, the technical features described in an open-ended manner include both closed-ended technical solutions composed of the listed features and open-ended technical solutions that include the listed features.

[0033] In this invention, numerical intervals (i.e., numerical ranges) are involved. Unless otherwise specified, the selected numerical distributions within the aforementioned numerical intervals are considered continuous and include the two endpoints (i.e., the minimum and maximum values) of the numerical range, as well as every value between these two endpoints. Unless otherwise specified, when a numerical interval refers only to integers within that interval, it includes the two endpoint integers of the numerical range, as well as every integer between the two endpoints. In this document, this is equivalent to directly listing every integer. For example, if t is an integer selected from 1 to 10, it means that t is any integer selected from the group of integers consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. Furthermore, when multiple ranges are provided to describe features or characteristics, these ranges can be merged. In other words, unless otherwise specified, the ranges disclosed herein should be understood to include any and all subranges to which they are included.

[0034] In this invention, percentage content refers to mass percentage for solid-liquid mixtures and solid-phase-solid mixtures, and volume percentage for liquid-phase-liquid mixtures, unless otherwise specified.

[0035] In this invention, percentage concentrations, unless otherwise specified, refer to the final concentration. The final concentration refers to the proportion of the added component in the system after the addition of that component.

[0036] In this invention, % (w / w) and wt% both represent weight percentage, % (v / v) refers to volume percentage, and % (w / v) refers to mass-volume percentage.

[0037] In this invention, "medicine" includes any agent, compound, composition, or mixture that provides physiological and / or pharmacological effects in vivo or in vitro, and often provides beneficial effects. The scope of the physiological and / or pharmacological effects produced by the "medicine" in vivo is not particularly limited; it may have systemic effects or only local effects. The activity of the "medicine" is not particularly limited; it may be an active substance that can interact with other substances or an inert substance that does not interact with other substances.

[0038] In this invention, "therapeutic effective amount" refers to the amount of the compound of this invention that will elicit a biological or medical response in an individual, such as the amount of the compound of this invention that brings positive physiological and / or pharmacological effects to an individual, including but not limited to reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression or preventing disease.

[0039] This embodiment provides a vonoprazan fumarate dry suspension, comprising a vonoprazan fumarate solid dispersion and excipients;

[0040] The vonoprazan fumarate solid dispersion is prepared by hot melt granulation of vonoprazan fumarate and a carrier material.

[0041] The carrier material is selected from one or both of hydroxypropyl cellulose and copovidone.

[0042] For vonoprazan fumarate, which has a strong bitter taste, this embodiment selected a suitable carrier material and prepared a vonoprazan fumarate solid dispersion by hot melt granulation. The vonoprazan fumarate dry suspension containing the above-mentioned vonoprazan fumarate solid dispersion can maintain a good dissolution rate of vonoprazan fumarate in a 120-minute simulated in vivo drug release dissolution medium, and can also maintain a low release of vonoprazan fumarate in a 2-minute artificial saliva medium. This ensures that the vonoprazan fumarate dry suspension has a very little bitter taste during administration, and successfully prepared vonoprazan fumarate, which has a strong bitter taste, into a dry suspension with good patient compliance.

[0043] Optionally, the weight ratio of vonoprazan fumarate to the carrier material is (1-10):(4-40). Further optionally, the weight ratio of vonoprazan fumarate to the carrier material is (1-10):(4-30). Further optionally, the weight ratio of vonoprazan fumarate to the carrier material can be 1:(2-6).

[0044] Optionally, the hot-melt granulation method is either hot-melt extrusion or hot-melt spraying. Optionally, hot-melt extrusion can be performed in a hot-melt extruder, and hot-melt spraying can be performed in a hot-melt spraying machine. By encapsulating the carrier material around vonoprazan fumarate using the hot-melt granulation method, the bitter taste of vonoprazan fumarate is prevented from directly contacting the taste buds, achieving a masking effect and improving patient compliance, especially for the elderly and children.

[0045] Optionally, a strip-shaped product can be extruded using a hot-melt extruder, which, after pulverization, yields a vonoprazan fumarate solid dispersion. In this case, due to the poor hygroscopicity of the selected carrier material, the aging problem commonly encountered during the pulverization process of vonoprazan fumarate solid dispersion under high humidity and high heat can be effectively solved, thereby significantly improving the stability of the drug.

[0046] Optionally, a fine powder can be sprayed out using a hot melt sprayer, which is a vonoprazan fumarate solid dispersion.

[0047] Optionally, the excipients include a first flavoring agent and a second flavoring agent. Adding flavoring agents can help mask flavors; the method is simple and low-cost.

[0048] The first flavoring agent is selected from one or more of sodium saccharin, sucrose, and aspartame;

[0049] The second flavoring agent is selected from one or more of orange powder flavoring, peach powder flavoring and vanilla flavoring.

[0050] Optionally, the excipients may also include one or more of fillers, suspending agents, and pH adjusters.

[0051] Optionally, the filler is selected from one or both of sorbitol and mannitol.

[0052] Optionally, the suspending agent is selected from one or more of xanthan gum, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, and sodium alginate. Preferably, the suspending agent is xanthan gum. Screening suspending agent materials helps improve the uniformity of suspension.

[0053] Optionally, the pH adjuster is selected from one or more of sodium citrate, sodium citrate, and sodium bicarbonate.

[0054] In this embodiment, sodium citrate can be anhydrous sodium citrate.

[0055] Vonoprazan fumarate is relatively poorly soluble, and traditional wet granulation methods for producing dry suspensions may result in poor suspension uniformity. However, the vonoprazan fumarate dry suspension of this invention exhibits excellent suspension uniformity after adding water, with no precipitation or stratification issues.

[0056] Optionally, the vonoprazan fumarate dry suspension comprises the following raw material components by weight percentage:

[0057]

[0058] The mass percentage of vonoprazan fumarate can be 1%, 3%, 5%, 8%, or 10%.

[0059] The mass percentage of the carrier material can be 4%, 10%, 15%, 20%, 30%, or 40%.

[0060] The mass percentage of the first flavoring agent can be 0.05%, 0.15%, 0.2%, 0.4%, 0.8%, 1%, 1.5%, 1.9%, or 2%.

[0061] The mass percentage of the second flavoring agent can be 0.05%, 0.08%, or 0.1%.

[0062] The filler can be 45%, 47%, 50%, 60%, 65%, 67%, 68%, 69%, 70%, 80%, or 90% by mass.

[0063] The mass percentage of the suspending agent can be 1.5%, 2%, 2.5%, 3%, 4%, or 5%.

[0064] The mass percentage of the pH adjuster can be 1%, 1.3%, 1.5%, 1.7%, 1.9%, 2%, 2.2%, 2.5%, or 3%.

[0065] The fumarate vonoprazan dry suspension of this embodiment can be packaged in unit doses, ensuring accurate dosage and convenient administration.

[0066] One embodiment of the present invention provides a method for preparing the above-mentioned vonoprazanol fumarate dry suspension, which includes the following steps:

[0067] S1. Take vonoprazan fumarate and carrier material, and prepare vonoprazan fumarate solid dispersion by hot melt granulation method.

[0068] Optionally, the hot melt granulation method is as described above, and will not be repeated here.

[0069] Optionally, when preparing vonoprazan fumarate solid dispersion by hot melt extrusion, the heating temperature for hot melt extrusion can be 110℃~150℃.

[0070] S2. Mix vonoprazan fumarate solid dispersion and excipients to prepare vonoprazan fumarate dry suspension.

[0071] Optionally, mixing the vonoprazan fumarate solid dispersion and excipients may include the following steps:

[0072] The first flavoring agent is dissolved in water to obtain an aqueous solution of the first flavoring agent;

[0073] The aqueous solution of filler, suspending agent and first flavoring agent was wet-granulated to obtain particulate matter;

[0074] Vonoprazan fumarate solid dispersion, particulate matter, pH adjuster, and second flavoring agent are mixed to obtain vonoprazan fumarate dry suspension.

[0075] Optionally, in wet granulation, the filler and suspending agent are first mixed at a stirring speed of 130 rpm to 160 rpm and a shearing speed of 1500 rpm to 1800 rpm for 3 to 5 minutes. Then, an aqueous solution of the first flavoring agent is added, which acts as a binder to prepare the wet soft material. The wet soft material is then granulated, dried, and dry granulated to obtain granules.

[0076] Optionally, the mixing conditions for the vonoprazan fumarate solid dispersion, particulate matter, pH adjuster, and second flavoring agent include: a rotation speed of 13 rpm to 15 rpm and a mixing time of 5 min to 10 min.

[0077] The fumarate vonoprazan dry suspension prepared in this embodiment releases less than 2% in artificial saliva within 10 minutes, significantly improving the strong bitter taste of fumarate vonoprazan and thus enhancing patient compliance, especially in the elderly and children. This provides a new (P-CAB) treatment option for elderly patients, children, and those with dysphagia. Furthermore, the suspension exhibits good homogeneity after adding water, with no precipitation or stratification issues, and is packaged in unit doses, ensuring accurate dosage and convenient administration.

[0078] The following description, in conjunction with specific embodiments and comparative examples, will provide further details. Unless otherwise specified, all raw materials and instruments used in the following specific embodiments are commercially available. Unless otherwise specified, all processes involved are conventionally selected by those skilled in the art.

[0079] Example 1

[0080] This embodiment provides a vonoprazan fumarate dry suspension and its preparation method, the steps of which are as follows:

[0081] Step 1: Refer to Table 1 and weigh each raw material component, where the content is expressed as a percentage by mass.

[0082] Table 1

[0083]

[0084]

[0085] Step 2: Take copovidone (S630) and heat it to 110°C to melt it, obtaining a molten liquid. While stirring, add vonoprazan fumarate to the molten liquid and stir until homogeneous, obtaining a mixture. Add the mixture to a hot melt extruder to prepare a strip-shaped product. Crush the strip-shaped product and pass it through a 40-mesh sieve to obtain a vonoprazan fumarate solid dispersion.

[0086] Step 3: Add water to aspartame and dissolve to obtain an aspartame aqueous solution. Add sorbitol to a wet granulator, then add xanthan gum, and start stirring and shearing (stirring speed 150 rpm, shearing speed 1500 rpm) for 3 minutes. Add the above aspartame aqueous solution to obtain a wet soft mass. The above wet soft mass is granulated through a 30-mesh oscillating granulator, dried in a fluidized bed to a moisture content of 2 wt%, and then granulated again through a 30-mesh oscillating granulator to obtain granules. In a three-dimensional mixer, mix the above vonoprazan fumarate solid dispersion, granules, anhydrous sodium citrate, and peach powder flavoring at 13 rpm for 10 minutes. Using a granulation packaging machine, package into bags of different sizes (0.5g, 1g, 2g, etc.) according to different dosages to obtain vonoprazan fumarate dry suspension.

[0087] Example 2

[0088] This embodiment provides a vonoprazan fumarate dry suspension and its preparation method, the steps of which are as follows:

[0089] Step 1: Refer to Table 2 and weigh each raw material component, where the content is expressed as a percentage by mass.

[0090] Table 2

[0091]

[0092]

[0093] Step 2: Take hydroxypropyl cellulose (HPC) and heat it to 140°C to melt it, obtaining a molten liquid. While stirring, add vonoprazan fumarate to the molten liquid and stir until homogeneous, obtaining a mixture. Add the mixture to a hot melt extruder to prepare a strip-shaped product. Crush the strip-shaped product and pass it through a 40-mesh sieve to obtain a vonoprazan fumarate solid dispersion.

[0094] Step 3: Add water to sodium saccharin and dissolve to obtain a sodium saccharin aqueous solution. Add sorbitol to a wet granulator, then add xanthan gum, and start stirring and shearing (stirring speed 150 rpm, shearing speed 1500 rpm) for 3 minutes. Add the above sodium saccharin aqueous solution to obtain a wet soft mass. The above wet soft mass is granulated through a 30-mesh vibrating granulator, dried in a fluidized bed to a moisture content of 2 wt%, and then granulated again through a 30-mesh vibrating granulator to obtain granules. In a three-dimensional mixer, mix the above vonoprazan fumarate solid dispersion, granules, anhydrous sodium citrate, and orange powder flavoring at 13 rpm for 10 minutes. Using a granulation packaging machine, package the granules into bags of different sizes (0.5g, 1g, 2g, etc.) according to different dosages to obtain vonoprazan fumarate dry suspension.

[0095] Example 3

[0096] This embodiment provides a vonoprazan fumarate dry suspension and its preparation method, the steps of which are as follows:

[0097] Step 1: Refer to Table 3 and weigh each raw material component, where the content is expressed as a percentage by mass.

[0098] Table 3

[0099]

[0100]

[0101] Step 2: Take hydroxypropyl cellulose (HPC) and heat it to 130°C to melt it, obtaining a molten liquid. While stirring, add vonoprazan fumarate to the molten liquid and stir until homogeneous, obtaining a mixture. Add the mixture to a hot melt extruder to prepare a strip-shaped product. Crush the strip-shaped product and pass it through a 40-mesh sieve to obtain a vonoprazan fumarate solid dispersion.

[0102] Step 3: Add water to sodium saccharin and dissolve to obtain a sodium saccharin aqueous solution. Add mannitol to a wet granulator, then add xanthan gum, and start stirring and shearing (stirring speed 150 rpm, shearing speed 1500 rpm) for 3 minutes. Add the above sodium saccharin aqueous solution to obtain a wet soft mass. The above wet soft mass is granulated through a 30-mesh vibrating granulator, dried in a fluidized bed to a moisture content of 2 wt%, and then granulated again through a 30-mesh vibrating granulator to obtain granules. In a three-dimensional mixer, mix the above vonoprazan fumarate solid dispersion, granules, anhydrous sodium citrate, and peach powder flavoring at 13 rpm for 10 minutes. Using a granulation packaging machine, package the granules into bags of different sizes (0.5g, 1g, 2g, etc.) according to different dosages to obtain vonoprazan fumarate dry suspension.

[0103] Example 4

[0104] This embodiment provides a vonoprazan fumarate dry suspension and its preparation method, the steps of which are as follows:

[0105] Step 1: Refer to Table 4 and weigh each raw material component, where the content is expressed as a percentage by mass.

[0106] Table 4

[0107]

[0108]

[0109] Step 2: Take hydroxypropyl cellulose (HPC) and heat it to 150°C to melt it, obtaining a molten liquid. While stirring, add vonoprazan fumarate to the molten liquid and stir until homogeneous, obtaining a mixture. Add the mixture to a hot melt extruder to prepare a strip-shaped product. Crush the strip-shaped product and pass it through a 40-mesh sieve to obtain a vonoprazan fumarate solid dispersion.

[0110] Step 3: Add water to sodium saccharin and dissolve to obtain a sodium saccharin aqueous solution. Add sorbitol to a wet granulator, then add xanthan gum, and start stirring and shearing (stirring speed 150 rpm, shearing speed 1500 rpm) for 3 minutes. Add the above sodium saccharin aqueous solution to obtain a wet soft mass. The above wet soft mass is granulated through a 30-mesh vibrating granulator, dried in a fluidized bed to a moisture content of 2 wt%, and then granulated again through a 30-mesh vibrating granulator to obtain granules. In a three-dimensional mixer, mix the above vonoprazan fumarate solid dispersion, granules, anhydrous sodium citrate, and vanilla flavoring at 13 rpm for 10 minutes. Using a granulation packaging machine, package the granules into bags of different sizes (0.5g, 1g, 2g, etc.) according to different dosages to obtain vonoprazan fumarate dry suspension.

[0111] Example 5

[0112] This embodiment provides a vonoprazan fumarate dry suspension and its preparation method, the steps of which are as follows:

[0113] Step 1: Refer to Table 5 and weigh each raw material component, where the content is expressed as a percentage by mass.

[0114] Table 5

[0115]

[0116]

[0117] Step 2: Take copovidone (S630) and heat it to 110°C to melt it, obtaining a molten liquid. While stirring, add vonoprazan fumarate to the molten liquid and stir until homogeneous, obtaining a mixture. Add the mixture to an MS220 hot melt sprayer, which conveys it through a twin-screw extruder to a two-flow gas spray gun. The atomized droplets are then mixed with chilled air (-10°C to 15°C) and solidified into a solid powder, yielding a vonoprazan fumarate solid dispersion.

[0118] Step 3: Add water to sodium saccharin and dissolve to obtain a sodium saccharin aqueous solution. Add sorbitol to a wet granulator, then add hydroxypropyl methylcellulose E15, and start stirring and shearing (stirring speed 150 rpm, shearing speed 1500 rpm) for 3 minutes. Add the above sodium saccharin aqueous solution to obtain a wet soft mass. The above wet soft mass is granulated through a 30-mesh vibrating granulator, dried in a fluidized bed to a moisture content of 2 wt%, and then granulated again through a 30-mesh vibrating granulator to obtain granules. In a three-dimensional mixer, mix the above vonoprazan fumarate solid dispersion, granules, anhydrous sodium citrate, and orange powder flavoring at 13 rpm for 10 minutes. Using a granulation packaging machine, package into bags of different sizes (0.5g, 1g, 2g, etc.) according to different dosages to obtain vonoprazan fumarate dry suspension.

[0119] Example 6

[0120] This embodiment provides a vonoprazan fumarate dry suspension and its preparation method, the steps of which are as follows:

[0121] Step 1: Refer to Table 6 and weigh each raw material component, where the content is expressed as a percentage by mass.

[0122] Table 6

[0123]

[0124]

[0125] Step 2: Take hydroxypropyl cellulose (HPC) and heat it to 140°C to melt it, obtaining a molten liquid. While stirring, add vonoprazan fumarate to the molten liquid and stir until homogeneous, obtaining a mixture. Add the mixture to a hot melt extruder to prepare a strip-shaped product. Crush the strip-shaped product and pass it through a 40-mesh sieve to obtain a vonoprazan fumarate solid dispersion.

[0126] Step 3: Add water to sucrose and dissolve to obtain a sucrose aqueous solution. Add mannitol to a wet granulator, then add sodium alginate, and start stirring and shearing (stirring speed 150 rpm, shearing speed 1500 rpm) for 3 minutes. Add the above sucrose aqueous solution to obtain a wet soft mass. The above wet soft mass is granulated through a 30-mesh vibrating granulator, dried in a fluidized bed to a moisture content of 2 wt%, and then granulated again through a 30-mesh vibrating granulator to obtain granules. In a three-dimensional mixer, mix the above vonoprazan fumarate solid dispersion, granules, sodium bicarbonate, and orange powder flavoring at 13 rpm for 10 minutes. Using a granulation packaging machine, package the granules into bags of different sizes (0.5g, 1g, 2g, etc.) according to different dosages to obtain vonoprazan fumarate dry suspension.

[0127] Comparative Example 1

[0128] This comparative example provides a vonoprazan fumarate dry suspension and its preparation method, the steps of which are as follows:

[0129] Step 1: Refer to Table 7 and weigh each raw material component, where the content is expressed as a percentage by mass.

[0130] Table 7

[0131]

[0132]

[0133] Step 2: Mix vonoprazan fumarate, sucrose, mannitol, and xanthan gum evenly, and add an ethanol aqueous solution (50% by volume) as a binder to prepare a wet soft mass. The wet soft mass is then granulated using a 30-mesh vibrating granulator, dried in a fluidized bed to a moisture content of 2 wt%, and finally granulated again using a 30-mesh vibrating granulator to obtain granules. These granules are then mixed with micronized silica gel in a three-dimensional mixer at 13 rpm for 10 minutes. Using a granulation packaging machine, the granules are packaged into bags of different sizes (0.5g, 1g, 2g, etc.) according to different dosages to obtain vonoprazan fumarate dry suspension.

[0134] Comparative Example 2

[0135] This comparative example provides a vonoprazan fumarate dry suspension and its preparation method, the steps of which are as follows:

[0136] Step 1: Refer to Table 8 and weigh each raw material component, where the content is expressed as a percentage by mass.

[0137] Table 8

[0138]

[0139] Step 2: Take polyethylene glycol (PEG6000) and heat it to 80°C to melt it, obtaining a molten liquid. While stirring, add vonoprazan fumarate to the molten liquid and stir until homogeneous, obtaining a mixture. Add the mixture to a hot melt extruder to prepare a strip-shaped product. Crush the strip-shaped product and pass it through a 40-mesh sieve to obtain a vonoprazan fumarate solid dispersion.

[0140] Step 3: Add water to sodium saccharin and dissolve to obtain a sodium saccharin aqueous solution. Add sorbitol to a wet granulator, then add xanthan gum, and start stirring and shearing (stirring speed 150 rpm, shearing speed 1500 rpm) for 3 minutes. Add the above sodium saccharin aqueous solution to obtain a wet soft mass. The above wet soft mass is granulated through a 30-mesh vibrating granulator, dried in a fluidized bed to a moisture content of 2 wt%, and then granulated again through a 30-mesh vibrating granulator to obtain granules. In a three-dimensional mixer, mix the above vonoprazan fumarate solid dispersion, granules, anhydrous sodium citrate, and orange powder flavoring at 13 rpm for 10 minutes. Using a granulation packaging machine, package the granules into bags of different sizes (0.5g, 1g, 2g, etc.) according to different dosages to obtain vonoprazan fumarate dry suspension.

[0141] Comparative Example 3

[0142] This comparative example provides a vonoprazan fumarate dry suspension and its preparation method, the steps of which are as follows:

[0143] Step 1: Refer to Table 9 and weigh each raw material component, where the content is expressed as a percentage by mass.

[0144] Table 9

[0145]

[0146]

[0147] Step 2: Take stearic acid and heat it to 80°C to melt it, obtaining a molten liquid. While stirring, add vonoprazan fumarate to the molten liquid and stir until homogeneous, obtaining a mixture. Add the mixture to a hot melt extruder to prepare a strip-shaped product. Crush the strip-shaped product and pass it through a 40-mesh sieve to obtain a vonoprazan fumarate solid dispersion.

[0148] Step 3: Add water to sodium saccharin and dissolve to obtain a sodium saccharin aqueous solution. Add sorbitol to a wet granulator, then add xanthan gum, and start stirring and shearing (stirring speed 150 rpm, shearing speed 1500 rpm) for 3 minutes. Add the above sodium saccharin aqueous solution to obtain a wet soft mass. The above wet soft mass is granulated through a 30-mesh vibrating granulator, dried in a fluidized bed to a moisture content of 2 wt%, and then granulated again through a 30-mesh vibrating granulator to obtain granules. In a three-dimensional mixer, mix the above vonoprazan fumarate solid dispersion, granules, anhydrous sodium citrate, and orange powder flavoring at 13 rpm for 10 minutes. Using a granulation packaging machine, package the granules into bags of different sizes (0.5g, 1g, 2g, etc.) according to different dosages to obtain vonoprazan fumarate dry suspension.

[0149] Comparative Example 4

[0150] This comparative example provides a vonoprazan fumarate dry suspension and its preparation method, the steps of which are as follows:

[0151] Step 1: Refer to Table 10 and weigh each raw material component, where the content is expressed as a percentage by mass.

[0152] Table 10

[0153]

[0154]

[0155] Step 2: Add water to sodium saccharin and dissolve to obtain a sodium saccharin aqueous solution. Add sorbitol to a wet granulator, then add vonoprazan fumarate, hydroxypropyl cellulose (HPC), and xanthan gum. Start stirring and shearing (stirring speed 150 rpm, shearing speed 1500 rpm) and mix for 3 minutes. Add the above sodium saccharin aqueous solution to obtain a wet soft mass. The above wet soft mass is granulated through a 30-mesh vibrating granulator, dried in a fluidized bed to a moisture content of 2 wt%, and then granulated again through a 30-mesh vibrating granulator to obtain granules. In a three-dimensional mixer, mix the above granules, anhydrous sodium citrate, and orange powder flavoring at 13 rpm for 10 minutes. Use a granulation packaging machine to package it into bags of different sizes (0.5g, 1g, 2g, etc.) according to different dosages to obtain vonoprazan fumarate dry suspension.

[0156] Test Example 1: Tester's Taste Test

[0157] The fumarate vonoprazan dry suspensions prepared in Examples 1-6 and Comparative Examples 1-4 were respectively suspended in warm water at approximately 37°C. Twenty-four testers were selected to try the suspensions and evaluate the taste by choosing one of the following four options: 1) sweet and good taste; 2) sweet and average taste; 3) sweet and slightly bitter; 4) slightly sweet and rather bitter. The results are shown in Table 11.

[0158] Table 11

[0159]

[0160]

[0161] As shown in Table 11:

[0162] 1) In Comparative Example 1, vonoprazan fumarate was directly wet-granulated with excipients. Despite the use of a large amount of flavoring agent, the bitter taste of vonoprazan fumarate could not be masked. Comparative Example 4 also failed to mask the bitter taste of vonoprazan fumarate.

[0163] 2) The main difference between Comparative Example 2 and Example 2 is that the carrier material used is different. However, the vonoprazan fumarate dry suspension of Comparative Example 2 has a more obvious bitter taste, indicating that the use of carrier material has an important impact on the release of vonoprazan fumarate.

[0164] Test 2: Electronic Tongue Taste Test

[0165] Instrument Model: TS-5000Z

[0166] Manufacturer: INSENT

[0167] Taste analysis sensors: 1) Sourness sensor (CA0); 2) Bitterness sensor (C00); 3) Astringency sensor (AE1); 4) Umami sensor (CAA); 5) Saltiness sensor (CT0);

[0168] Evaluation Method: Weber's theorem (sensory threshold law) was employed, using taste-sensing electrodes and focusing on taste analysis. Different membrane sensor arrays recorded the potential difference between the electrodes and a reference electrode. The difference threshold was proportional to the intensity of the standard stimulus.

[0169] The bitter aftertaste reflects the persistence and duration of bitterness (simulating the lingering bitterness in the mouth after taking medicine with water). The astringent aftertaste reflects the persistence and duration of astringency.

[0170] The fumarate vonoprazan dry suspensions prepared in Examples 1 (S1), 4 (S4), Comparative Example 1 (D1), and 4 (D4), as well as the blank sample (KB), were suspended in warm water at approximately 37°C, and the taste was tested using an electronic tongue. All data are absolute output values ​​based on artificial saliva (reference solution). The electronic tongue test simulates the state of artificial saliva in the human mouth when only saliva is present. The results are shown in Table 12.

[0171] Table 12

[0172]

[0173] Table 12 shows that, compared to the blank sample, the vonoprazan fumarate dry suspensions of Examples 1 (S1), 4 (S4), Comparative Example 1 (D1), and Comparative Example 4 (D4) all exhibited a bitter taste. Comparative Example 1 (D1) and Comparative Example 4 (D4) showed an extremely bitter taste, especially with a significant bitter and astringent aftertaste. Examples 1 (S1) and 4 (S4) showed some bitterness and astringent aftertaste, but these were significantly improved, which could significantly improve patient compliance.

[0174] Test Example 3: Determination of Dissolution Curve in Dissolution Medium

[0175] (1) Instruments and reagents

[0176] Instrument: RC12AD Intelligent Drug Dissolution Tester

[0177] Test drug: Vonopram fumarate dry suspension

[0178] Sample amounts: 0.5g for Example 3, 5.0g for Example 4, and 1.0g for other examples and comparative examples.

[0179] (2) Detection method: Ultraviolet-visible spectrophotometry

[0180] Detection wavelength: 326nm

[0181] Dissolution method: Paddle method

[0182] Dissolution medium: water

[0183] Medium volume: 1000 mL

[0184] Rotation speed: 50 rpm

[0185] Sampling time points: 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 90 min, 120 min

[0186] Test solution: Take 20 mL of solution from each sampling point, filter, take 5 mL of the filtrate, put it in a 25 mL volumetric flask, and dilute to the mark with the dissolution medium.

[0187] Reference solution: Weigh approximately 25 mg of vonoprazan fumarate reference standard accurately, place it in a 1000 mL volumetric flask, add dissolution medium, sonicate to dissolve, dilute to the mark with dissolution medium, and shake well; accurately measure 10 mL of the above solution, place it in a 25 mL volumetric flask, dilute to the mark with dissolution medium, and shake well to obtain the reference solution.

[0188] The results of the dissolution curve determination in the dissolution medium are shown in Table 13 and Figure 1 As shown.

[0189] Table 13

[0190]

[0191]

[0192] Test Example 4: Determination of Release Curve of Artificial Saliva Medium

[0193] (1) Instruments and reagents

[0194] Instrument: SHZ-82A Digital Display Constant Temperature Water Bath Oscillator (Shandong Oulaibo Instrument Co., Ltd.)

[0195] Test drug: Vonopram fumarate dry suspension

[0196] Sample quantities: 50 mg of vonoprazan fumarate dry suspension was taken in Example 3, 500 mg of vonoprazan fumarate dry suspension was taken in Example 4, and 100 mg of samples were taken in other examples and comparative examples.

[0197] (2) Detection method: Ultraviolet-visible spectrophotometry

[0198] Detection wavelength: 326nm

[0199] Release medium: artificial saliva

[0200] Media volume: 15mL

[0201] Speed: 60 rpm

[0202] Sampling time points: 2 min, 5 min, 10 min, 15 min

[0203] Test solution: Take 1 mL of solution from each sampling point, filter, accurately measure 0.5 mL of the filtrate, place it in a 5 mL volumetric flask, and dilute with water to the mark.

[0204] Reference solution: Refer to the reference solution under test 3.

[0205] The results of the artificial saliva release curve determination are shown in Table 14 and Figure 2 As shown.

[0206] Table 14

[0207]

[0208]

[0209] Dissolution profile determination in dissolution media primarily examines the dissolution rate of a drug in an aqueous medium simulating in vivo drug release, evaluating the drug's solubility in vivo. Artificial saliva release profile determination primarily examines the release rate of a drug during water dissolution and dispersion, and during swallowing, evaluating the masking effect of bitter taste and patient compliance.

[0210] From Table 13, Table 14, Figure 1 and Figure 2 It can be seen that:

[0211] 1) In artificial saliva medium, the vonoprazan fumarate dry suspensions of Examples 1-6 showed less than 2% drug release after 5 minutes and less than 5% after 10 minutes. However, in an aqueous medium simulating in vivo drug release, a relatively rapid release of over 85% was achieved within 45 minutes. This indicates that the vonoprazan fumarate dry suspension of the present invention dissolves well in vivo, reduces the bitter taste perceived by taste buds, and improves patient compliance.

[0212] 2) In Comparative Example 2, the vonoprazan fumarate dry suspension showed less than 2% drug release in artificial saliva medium at 2 minutes and more than 5% at 5 minutes. The taste buds could not perceive bitterness for longer than the time required for the drug to disperse in water and be swallowed, thus failing to mask the taste. Comparative Examples 1 and 4 showed no taste-masking effect at all.

[0213] 3) Although the vonoprazan fumarate dry suspension of Comparative Example 3 has a significant taste-masking effect in artificial saliva medium, its release rate in simulated in vivo is too slow.

[0214] This invention utilizes an electronic tongue sensor for comprehensive taste evaluation of the product. The instrument's artificial membrane employs an electronic sensor for detection, resulting in a more objective and reproducible evaluation method. Simultaneously, a method for testing drug release in artificial saliva media was established to assess the drug release rate during water dissolution and dispersion, as well as during swallowing, evaluating taste masking effectiveness and patient compliance. These two evaluation methods provide a reference for taste evaluation of other products.

[0215] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0216] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the patent. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the patent for this invention shall be determined by the appended claims.

Claims

1. A vonoprazan fumarate dry suspension, characterized in that: Includes vonoprazan fumarate solid dispersion and excipients; The vonoprazan fumarate solid dispersion is prepared from vonoprazan fumarate and a carrier material by a hot melt granulation method; The carrier material is selected from one or both of hydroxypropyl cellulose and copovidone; The auxiliary materials include a first flavoring agent, a second flavoring agent, a filler, a suspending agent and a pH regulator; the first flavoring agent is selected from one or more of saccharin sodium, sucrose and aspartame; the second flavoring agent is selected from one or more of orange powder flavor, peach powder flavor and vanilla flavor; the filler is selected from one or both of sorbitol and mannitol; the suspending agent is selected from one or more of xanthan gum, hypromellose, sodium carboxymethylcellulose and sodium alginate; the pH regulator is selected from one or more of monosodium citrate, sodium citrate and sodium bicarbonate; The mass percentage of the vonoprazan fumarate in the raw material components of the vonoprazan fumarate dry suspension is 1% to 10%; the mass percentage of the carrier material in the raw material components of the vonoprazan fumarate dry suspension is 4% to 40%; the mass percentage of the first flavoring agent in the raw material components of the vonoprazan fumarate dry suspension is 0.05% to 2%; the mass percentage of the second flavoring agent in the raw material components of the vonoprazan fumarate dry suspension is The mass percentage of the filler in the raw material components of the vonoprazan fumarate dry suspension is 45% to 90%; the mass percentage of the suspending agent in the raw material components of the vonoprazan fumarate dry suspension is 1.5% to 5%; the mass percentage of the pH regulator in the raw material components of the vonoprazan fumarate dry suspension is 1% to 3%, and the mass ratio of the vonoprazan fumarate to the carrier material is 1: (2 to 6).

2. The vonoprazan fumarate dry suspension according to claim 1, characterized in that The hot melt granulation method is a hot melt extrusion method.

3. The vonoprazan fumarate dry suspension according to claim 1, characterized in that The hot melt granulation method is a hot melt spray method.

4. The vonoprazan fumarate dry suspension according to claim 1, characterized in that The raw material components include the following mass percentages:

5. The vonoprazan fumarate dry suspension according to claim 1, characterized in that The raw material components include the following mass percentages:

6. The vonoprazan fumarate dry suspension according to claim 1, characterized in that The raw material components include the following mass percentages:

7. The vonoprazan fumarate dry suspension according to claim 1, characterized in that The raw material components include the following mass percentages:

8. The vonoprazan fumarate dry suspension according to claim 1, characterized in that The raw material components include the following mass percentages:

9. The vonoprazan fumarate dry suspension according to claim 1, characterized in that: The raw material components include the following mass percentages:

10. A method for preparing the vonoprazan fumarate dry suspension according to any one of claims 1 to 9, characterized in that: The following steps are involved: Taking the vonoprazan fumarate and a carrier material, preparing a vonoprazan fumarate solid dispersion by a hot melt granulation method; The vonoprazan fumarate solid dispersion and auxiliary materials are mixed to prepare a vonoprazan fumarate dry suspension.

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