Therapeutic agent for gastroesophageal reflux disease with improved dosing convenience using water-insoluble polymer

Abstract

The present invention relates to an oral pharmaceutical composition comprising a therapeutic agent for gastroesophageal reflux disease, which uses a water-insoluble polymer to mask bitterness and improve dosing convenience. The composition according to the present invention can improve dosing convenience for elderly patients suffering from gastrointestinal diseases and patients complaining of dysphagia symptoms.

Description

A treatment for gastroesophageal reflux disease that improves ease of administration using water-insoluble polymers

[0001] The present invention relates to an oral pharmaceutical composition comprising a treatment for gastroesophageal reflux disease that uses a water-insoluble polymer to mask bitterness and improve ease of administration.

[0002] Although stomach acid plays positive roles such as protein digestion and sterilization of microorganisms in food, it is highly acidic with a pH of about 1 to 2; therefore, excessive secretion of stomach acid or reflux into the esophagus can cause gastroesophageal reflux disease (GERD). Generally, gastroesophageal reflux disease and gastric ulcer disease are characterized by causing heartburn and abdominal pain in patients even at normal times, but the most significant characteristic of the disease is the onset of discomfort accompanied by heartburn and acid reflux symptoms within 30 minutes after eating.

[0003] Proton-pump inhibitors (PPIs) have been widely used as treatments for gastroesophageal reflux disease (GERD). While PPIs are highly effective in inhibiting acid secretion, they require activation by acid, resulting in a delayed onset of action. Furthermore, their short half-life of approximately 90 minutes makes them prone to the recurrence of nocturnal symptoms. Additionally, existing PPIs are characterized by the requirement to be taken before meals; a disadvantage is that if taken after a meal, the drug breaks down rapidly in the acidic gastric environment created by the previous meal, preventing the attainment of sufficient therapeutic effect. Due to distinct limitations in pharmacokinetic characteristics, such as varying bioavailability depending on food intake, there is a demand for the development of treatments for gastric acid-related diseases based on new mechanisms to overcome these drawbacks.

[0004] The demand for P-CABs (Potassium-Competitive Acid Blockers), drugs that compensate for these shortcomings, is increasing. As competitive cation inhibitors, P-CABs [inject potassium (K] into] the proton pump acting at the terminal stage of gastric acid secretion + It has a mechanism that potently inhibits gastric acid secretion by competitively binding to ions. It is characterized by its rapid and long-lasting inhibitory effect on gastric acid secretion due to competitive and reversible binding to proton pumps. Additionally, a significant advantage of P-CABs is that they can be taken regardless of meals. In Korea, drugs containing P-CAB components as the main ingredient are being released, including K-Cap (Tegoprazan, HK Innoen).

[0005] Meanwhile, there is an increasing demand for the development of orally disintegrating tablets that rapidly disintegrate in the mouth with a small amount of water to produce an effect, for elderly patients who develop gastrointestinal diseases due to taking large amounts of medication, as well as patients with gastrointestinal diseases for other reasons and patients who complain of dysphagia, which makes it difficult to swallow medication without water.

[0006] One object of the present invention is to provide an oral pharmaceutical composition comprising vonoprazan or a pharmaceutically acceptable salt thereof and a granule portion comprising a water-insoluble polymer.

[0007] However, the technical problems that the present invention aims to solve are not limited to those mentioned above, and other unmentioned problems will be clearly understood by those skilled in the art from the description below.

[0008] To achieve the objectives of the present invention, the present invention provides an oral pharmaceutical composition comprising vonoprazan or a pharmaceutically acceptable salt thereof; and a water-insoluble polymer.

[0009] Specifically, the present invention provides an oral pharmaceutical composition comprising a granule portion comprising vonoprazan or a pharmaceutically acceptable salt thereof and a water-insoluble polymer, wherein the water-insoluble polymer is included in an amount of 17% to 47% by weight relative to the total weight of the granule portion.

[0010] In the present invention, the vonoprazan is a compound named 1-[5-(2-fluorophenyl)-1-[(pyridine-3-yl)sulfonyl]-1H-pyrrole-3-yl]-N-methylmethaneamine, which is a drug that effectively inhibits gastric acid secretion by competitively blocking potassium ions from binding to the enzyme (H+ / K+-ATPase) involved in gastric acid secretion. Vonoprazan is used for the treatment of gastric ulcers, duodenal ulcers, and reflux esophagitis, as well as for the prevention of gastric ulcers when administering low-dose aspirin.

[0011] In the present invention, pharmaceutically acceptable salts of vonoprazan refer to salts prepared using organic or inorganic acids or bases that are non-toxic or have low toxicity, and preferably, the pharmaceutically acceptable salt of vonoprazan may be vonoprazan fumarate, but is not limited thereto.

[0012] In the present invention, the water-insoluble polymer refers to a polymer capable of performing a bitterness-blocking function by being substantially insoluble or having a very slow dissolution rate under neutral or acidic conditions, and includes an enteric polymer that dissolves in a pH-dependent manner. The water-insoluble polymer of the present invention may be one or more selected from the group consisting of methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, aminoalkyl methacrylate copolymer, dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and ethyl cellulose, but is not limited thereto. Specifically, the water-insoluble polymer of the present invention may be, for example, a methacrylate copolymer including Eudragit L100, L30-D55, FL 30D-55, etc.; a cationic methacrylate copolymer including Eudragit E100, EPO, etc. It may be one or more selected from the group consisting of HPMC series enteric polymers including HPMC-P, HPMC-AS, etc.

[0013] The granular portion of the present invention can effectively shield the bitter taste of vonoprazan or its pharmaceutically acceptable salts by including a water-insoluble polymer.

[0014] In one embodiment of the present invention, the granule portion of the present invention may be manufactured as wet granules or dry granules.

[0015] In the present invention, the granule portion comprising vonoprazan or a pharmaceutically acceptable salt thereof and a water-insoluble polymer can be manufactured using various granule manufacturing methods known in the pharmaceutical field, specifically by methods such as a high shear mixer (HSM), a fluid bed granulator, and a spray drying process.

[0016] In one embodiment of the present invention, the granules of the present invention may be prepared by spraying a bitter-blocking spray containing a water-insoluble polymer onto vonoprazan or a pharmaceutically acceptable salt thereof alone, or a mixture of vonoprazan or a pharmaceutically acceptable salt thereof and an excipient.

[0017] In addition, in one embodiment of the present invention, the granule portion of the present invention may be prepared by spraying a bitter-blocking spray solution containing a water-insoluble polymer in vonoprazan or its pharmaceutically acceptable salt alone, or a mixture of vonoprazan or its pharmaceutically acceptable salt and an excipient, using a fluid granulator.

[0018] In one embodiment of the present invention, the water-insoluble polymer (based on solid content) may be included in an amount of about 15% to about 49% by weight, about 16% to about 48.5% by weight, about 17% to about 48.5% by weight, about 17% to about 48% by weight, about 18% to about 48.5% by weight, about 18% to about 48% by weight, about 17% to about 47% by weight, about 18% to about 47% by weight, or preferably about 19% to about 47% by weight, relative to the total weight of the granule portion.

[0019] In the composition of the present invention, if the content of the water-insoluble polymer is less than about 17 weight%, the bitterness shielding effect is insufficient, and if it exceeds about 47 weight%, there is a problem that the suitability as an orally disintegrating tablet or chewable tablet is reduced due to a decrease in the dissolution rate.

[0020] In the present invention, "about" means that for a specific numerical value or numerical range, it includes a variation within ±3% of said value or range. This range of variation is intended to include a range that may occur due to measurement errors, differences in experimental conditions, deviations in raw material characteristics, unavoidable deviations in the manufacturing process, or conventional technical tolerances.

[0021] The bitterness-shielding spray solution comprising the water-insoluble polymer of the present invention may be prepared using a water-insoluble polymer in the form of a solution or a powder. When using a water-insoluble polymer in the form of a solution, the bitterness-shielding spray solution may be prepared by mixing purified water or an organic solvent with a weight ratio of at least 10:0 to a maximum of 10:10 relative to the water-insoluble polymer solution; when using a water-insoluble polymer in the form of a powder, the bitterness-shielding spray solution may be prepared such that the ratio of solids in the bitterness-shielding spray solution is 10 to 40% (w / w). In one embodiment of the present invention, when the bitterness-shielding spray solution of the present invention is prepared using a water-insoluble polymer solution having a solid ratio of 30% (w / w), the bitterness-shielding spray solution may be a solution in which the water-insoluble polymer solution is mixed with purified water in a weight ratio of 10:1.

[0022] In one embodiment of the present invention, when the bitterness-shielding spray solution of the present invention is manufactured using a water-insoluble polymer in powder form, the bitterness-shielding spray solution may be a solution in which a water-insoluble polymer powder and an organic solvent are mixed in a weight ratio of 1:4 such that the amount of water-insoluble polymer solids in the total mass of the bitterness-shielding spray solution is 20% (w / w).

[0023] According to one embodiment of the present invention, the organic solvent may be ethanol, acetone, IPA, or a mixture thereof, but is not limited thereto.

[0024] In one embodiment of the present invention, the composition of the present invention may further include a sweetener.

[0025] In the present invention, the sweetener may be i) included in the granule portion, ii) included in the post-mixing portion, or iii) included in both the granule portion and the post-mixing portion.

[0026] In one embodiment of the present invention, the composition of the present invention may additionally include one or more sweeteners in the bitterness-blocking spray liquid to maximize the sweetening effect.

[0027] In one embodiment of the present invention, the composition of the present invention may further include a post-mixing part containing a sweetener for effective bitterness shielding.

[0028] In one embodiment of the present invention, the composition of the present invention may include a granule portion and a post-mixing portion.

[0029] In one embodiment of the present invention, the sweetener may be one or more selected from the group consisting of tomatine, neotame, sucralose, advancem, monellin, steviol glycosides (e.g., one or more of stevioside, rebaudioside A, B, C, D, E, F, M or N, and dulcoside A), sugar, acesulfame potassium, aspartame, saccharin, cyclamate, alitame, xylitol, sorbitol, maltitol, and erythritol.

[0030] In one embodiment of the present invention, the sweetener may be included in an amount of 2 parts by weight or less, preferably 1.5 parts by weight or less, more preferably 0.2 to 1.5 parts by weight or less, based on 1 part by weight of vonoprazan or a pharmaceutically acceptable salt thereof, for example, 0.2 to 2 parts by weight, 0.3 to 2 parts by weight, 0.4 to 2 parts by weight, preferably 0.5 to 2 parts by weight, 0.2 to 1.8 parts by weight, 0.3 to 1.6 parts by weight, 0.4 to 1.5 parts by weight, or 0.5 to 1.5 parts by weight.

[0031] In one embodiment of the present invention, the sweetener may include i) a sweetener with a long-lasting sweetening effect or ii) a combination of a sweetener with a long-lasting sweetening effect and a sweetener with a rapid sweetening effect.

[0032] In the present invention, the sweetener is characterized by essentially including a sweetener that sustains a sweetening effect for a long time, and compositions containing only a sweetener that rapidly manifests a sweetening effect are excluded from the present invention.

[0033] In the present invention, the sweetener with a long-lasting sweetening effect is also referred to as a "long-lasting sweetener" or a "sweetener with long sweetness," and refers to a sweetener that has a longer duration of sweetness than sugar and has a long duration of sweetness. The sweetener with a long-lasting sweetening effect comprises, but is not limited to, one or more selected from the group consisting of tomatine, neotame, sucralose, advancem, monellin, and steviol glycosides (e.g., one or more of stevioside, rebaudioside A, B, C, D, E, F, M, or N, and dulcoid A).

[0034] In the present invention, the sweetener that exhibits a rapid sweetening effect is also referred to as a "rapid sweetening effect sweetener," and means a sweetener that exhibits a rapid sweetening effect by having a short time to reach maximum sugar content. The sweetener that exhibits a rapid sweetening effect comprises one or more selected from the group consisting of sugar, acesulfame potassium, aspartame, saccharin, cyclamate, alitam, xylitol, sorbitol, maltitol, and erythritol, but is not limited thereto.

[0035] In one embodiment of the present invention, the sweetener having a long-lasting sweetening effect may be one or more of sucralose, tomatine, and neotame, and the sweetener having a rapid sweetening effect may be one or more of aspartame, acesulfame potassium, and saccharin.

[0036] In one embodiment of the present invention, the sweetener having a long-lasting sweetening effect may be included in an amount of 0.05 parts by weight or more, preferably 0.1 parts by weight or more, based on 1 part by weight of vonoprazan or a pharmaceutically acceptable salt thereof, and may be included, for example, in an amount of 0.05 to 1.5 parts by weight, 0.1 to 1.5 parts by weight, 0.1 to 1.2 parts by weight, 0.1 to 1 part by weight, 0.1 to 0.9 parts by weight, 0.1 to 0.8 parts by weight, or 0.1 to 0.75 parts by weight.

[0037] In one embodiment of the present invention, the granule portion of the composition may additionally include one or more selected from the group consisting of a diluent, a disintegrant, a flavoring agent, and a lubricant.

[0038] In one embodiment of the present invention, the composition further comprises a post-mixing unit, and the post-mixing unit may comprise one or more selected from the group consisting of a diluent, a disintegrant, a flavoring agent, and a lubricant.

[0039] The above diluent may be one or more selected from the group consisting of mannitol, microcrystalline cellulose, starch, lactose, or a combination of the above components (Patek ODT, F-Melt, Ludiflash). According to one embodiment of the present invention, the diluent may be Patek ODT or F-Melt, but is not limited thereto.

[0040] In addition, the diluent may be included in the granule portion and the post-mixing portion in an amount of 30 to 90 weight%, 35 to 85 weight%, or 40 to 80 weight% relative to the total weight of the composition to form a sufficient volume and ensure fluidity. Furthermore, the diluent included in the granule portion may be included in an appropriate amount of 1:0 to 1:5.3 weight parts relative to the main component so that the final tablet does not lose marketability as an orally disintegrating tablet due to the inclusion of an excessive amount of water-insoluble polymer for bitterness shielding to form granules.

[0041] The above disintegrant may be one or more selected from the group consisting of crospovidone, sodium croscarmellose, and sodium starch glycolate. Additionally, the disintegrant may be included in an amount of 1 to 15 weight%, 2 to 12.5 weight%, or 3 to 10 weight% based on the total weight of the composition to increase the disintegration rate of the oral pharmaceutical composition. According to one embodiment of the present invention, the disintegrant may be crospovidone, but is not limited thereto.

[0042] The above-mentioned flavoring agent serves to improve the user experience by blocking bad odors, off-flavors, or off-odors, or by masking unpleasant tastes. For example, it may be a fragrance, and may be one or more selected from the group consisting of plant-based, animal-based, natural, or synthetic fragrances such as lemon balm, parsley seed oil, lemongrass oil, fennel, menthol; vanilla oil and almond oil containing aldehydes; terpene-based fragrances such as DL-camphor and eucalyptol; lemon oil, peppermint oil and orange oil containing terpenes; apricot oil and peach oil containing lactones; and apple oil containing esters. According to one embodiment of the present invention, the above-mentioned flavoring agent may be L-menthol, but is not limited thereto.

[0043] The above lubricant may be one or more selected from the group consisting of magnesium stearate, sodium stearyl fumarate, calcium stearate, silicon dioxide, talc, sucrose fatty acid ester, hydrogenated vegetable oil, high melting point wax, glyceryl fatty acid esters, and glycerol dibehenate. According to one embodiment of the present invention, the lubricant may be magnesium stearate or sodium stearyl fumarate, but is not limited thereto.

[0044] In the present invention, the composition may not contain organic acids. Furthermore, the composition of the present invention, while not containing organic acids, has excellent bitterness shielding effect, excellent dissolution and disintegration, and manufacturing advantages such as excellent stability, excellent content uniformity, and flowability.

[0045] The present invention provides a pharmaceutical formulation comprising the composition of the present invention.

[0046] In one embodiment of the present invention, the pharmaceutical formulation of the present invention may be an orally disintegrating tablet or a chewable tablet. The method of forming the orally disintegrating tablet or the chewable tablet is not particularly limited, and a compression molding method using a rotary tablet press, a single-shot tablet press, or a hydraulic press may be used. The compression molding pressure is not particularly limited as long as it provides sufficient strength to the tablet.

[0047] In addition, in one embodiment of the present invention, the total weight of the pharmaceutical preparation may be 600 mg, preferably 500 mg or less, and accordingly, it is suitable for taking as an orally disintegrating tablet or a chewable tablet.

[0048] A pharmaceutical formulation comprising the composition of the present invention controls the dissolution rate of the active ingredient in the oral cavity through granulation by a water-insoluble polymer, and exhibits an excellent effect in which more than 80% of the active ingredient is dissolved under low pH conditions while effectively masking bitterness.

[0049]

[0050] In addition, the present invention provides a method for preparing an oral pharmaceutical composition comprising: (a) a step of forming a granule portion by spraying a bitter-suppressing spray containing a water-insoluble polymer onto a mixture of vonoprazan or a pharmaceutically acceptable salt thereof; or a mixture of vonoprazan or a pharmaceutically acceptable salt thereof and a diluent; and (b) a step of mixing the granule portion prepared in step (a) with a post-mixing portion; wherein the water-insoluble polymer in the composition is included in an amount of 17% to 47% by weight relative to the total weight of the granule portion.

[0051] The above-mentioned vonoprazan, its pharmaceutically acceptable salt, diluent, water-insoluble polymer, and bitterness-blocking spray are as described above.

[0052] In step (a) above, the spraying of the spray liquid for high-molecular shielding can be performed by any method known in the art.

[0053] In one embodiment of the present invention, a sweetener may be i) included in a bitterness-shielding spray, ii) included in a post-mixing part, or iii) included in both the bitterness-shielding spray and the post-mixing part.

[0054] The above sweetener is as described above.

[0055] In one embodiment of the present invention, the post-mixing unit may include one or more selected from the group consisting of a diluent, a disintegrant, a flavoring agent, and a lubricant.

[0056] The above-mentioned diluent, disintegrant, flavoring agent, and lubricant are as described above.

[0057] In one embodiment of the present invention, the composition prepared by the above manufacturing method does not contain organic acid.

[0058] The composition of the present invention exhibits excellent disintegration rate and dissolution rate while effectively masking the bitter taste of vonoprazan, resulting in excellent sensory properties and palatability; thus, it can improve the convenience of administration for elderly patients suffering from gastrointestinal diseases and patients complaining of dysphagia. Furthermore, the composition of the present invention provides manufacturing advantages by possessing excellent stability through granulation and exhibiting excellent content uniformity and flowability.

[0059] Figure 1 is a graph showing the elution rate according to the ratio of water-insoluble polymer at pH 1.2.

[0060] Figure 2 is a graph showing the elution rate according to the ratio of water-insoluble polymer at pH 4.5.

[0061] Hereinafter, preferred embodiments and experimental examples are presented to aid in understanding the present invention. However, the following embodiments and experimental examples are provided merely to facilitate a better understanding of the present invention, and the scope of the present invention is not limited thereto.

[0062]

[0063] Examples 1 to 8 and Comparative Examples 1 to 2

[0064] To study the content of water-insoluble polymer used for high-quality shielding, Examples 1 to 8, Comparative Example 1, and Comparative Example 2 were prepared with the compositions and contents listed in Tables 1 and 2 below.

[0065] Specifically, vonoprazan or a pharmaceutically acceptable salt thereof was mixed with mannitol and then sieved through a 45 mesh sieve. In cases where mannitol was not included, vonoprazan or a pharmaceutically acceptable salt thereof alone was sieved through a 45 mesh sieve. The sieved material was placed into a fluid bed granulator (GREP Lab.1) and a bitter-suppressing spray was sprayed to produce granules. The above-mentioned bitterness-shielding spray solution was prepared by mixing a water-insoluble polymer (methacrylate copolymer or cationic methacrylate copolymer) and a sweetener (acesulfame K) in purified water or an organic solvent (ethanol). In the case where a methacrylate copolymer solution with a solid content ratio of 30% (w / w) was used as the water-insoluble polymer, the methacrylate copolymer solution was mixed with purified water at a weight ratio of 10:1 in Examples 1-7 and the Comparative Example. In Example 8, where a water-insoluble polymer in powder form was used, the methacrylate copolymer powder was mixed with an organic solvent at a weight ratio of 1:4 so that the solid content ratio of the bitterness-shielding spray solution was 20% (w / w). The specific conditions of the spraying process are as follows.

[0066]

[0067] <Process Conditions>

[0068] Supply air temperature: 67 ± 3 ℃

[0069] Product temperature: 31 ± 3 ℃

[0070] Injection speed: 45 rpm

[0071] Injection pressure: 1.5 bar

[0072]

[0073] The prepared granules were mixed with a diluent, a disintegrant, a sweetener, and a flavoring agent, and then a lubricant was added and mixed. The prepared final mixture was tableted to a hardness of 4–7 kp using a 10 mm round punch and a tablet press (Autotab-200TR, Ichihashiseiki).

[0074]

[0075] [Table 1]

[0076]

[0077]

[0078] [Table 2]

[0079]

[0080]

[0081] Experimental Example 1. Evaluation of dissolution rate according to ratio of water-insoluble polymer

[0082] To confirm the in vivo dissolution behavior of the tablets prepared in the examples and comparative examples, the dissolution rate was evaluated according to the following conditions.

[0083] [Elution Conditions]

[0084] Elution test solution: pH 1.2 solution, 900 mL or pH 4.5 solution, 900 mL

[0085] Dissolution device: Paddle

[0086] Rotation speed: 50 rpm

[0087] Temperature: 37 ℃

[0088]

[0089] [Liquid Chromatography Conditions]

[0090] Detector: Ultraviolet absorption spectrophotometer (Measurement wavelength: 230 nm)

[0091] Column: Gemini, NX-C18 (4.6 x 250 mm, 5 μm) or equivalent column

[0092] Flow rate: 1.0 mL / min

[0093] Column temperature: 35 ℃

[0094] Sample injection volume: 10 mL

[0095] Analysis time: 10 minutes

[0096] Mobile phase A : Buffer : MeOH : ACN = 720 : 250 : 30

[0097] Mobile phase B : Buffer : ACN = 300 : 700

[0098] Diluent: 50% ACN

[0099] Buffer: Approximately 4.2 g of potassium dihydrogen phosphate was weighed and dissolved in 1000 mL of purified water. Phosphoric acid was added to adjust the pH to 6.5 ± 0.05, and the solution was filtered through a 0.45 μm membrane filter.

[0100]

[0101] As a result, as shown in FIGS. 1 and 2, Examples 1 to 7 and Comparative Example 1 all disintegrated within 5 minutes in the dissolution port; however, when the ratio of water-insoluble polymer to the weight of the wet granule portion was 50% (w / w) or more, as in Comparative Example 1, a low dissolution rate of 80% or less was observed within 30 minutes under acidic conditions (pH 1.2 and pH 4.5), and under pH 1.2 solution conditions, the dissolution rate remained low at 80% or less even after 2 hours. Such low dissolution rates are disadvantageous when applied to chewable or orally disintegrating tablet formulations that require rapid disintegration in the oral cavity and rapid absorption under gastric conditions.

[0102]

[0103] Examples 9 to 15 and Comparative Examples 3 to 4

[0104] In order to select the type and ratio of sweeteners for more effective bitterness masking, Examples 9 to 15 and Comparative Examples 3 to 4 were prepared with the composition and content listed in Table 3 below. Specifically, Examples 9 to 15 and Comparative Examples 3 to 4 were prepared in the same manner as Example 1, but the final mixture prepared was formed into tablets with a total weight of 400 mg using a 10 mm diameter circular punch to a hardness of 7 kp.

[0105]

[0106] [Table 3]

[0107]

[0108]

[0109] Experimental Example 2. Sensory evaluation by type and ratio of sweetener

[0110] In this experimental example, the bitterness-shielding effect and palatability of the compositions in the examples and comparative examples were evaluated to select the type and ratio of sweeteners for more effective bitterness shielding.

[0111] Specifically, the degree of bitterness was scored when a 20 mg dose of vonoprazan was dissolved in the mouth of 45 men and women aged 20 to 45 years, and on a scale of 10, it was evaluated as 1-2 points: almost no bitterness, 3-4 points: mild bitterness, 5-6 points: moderate bitterness, 7-8 points: strong bitterness, and 9-10 points: very strong bitterness.

[0112] In addition, preference was evaluated using a rating scale (9-point scale) (9-point scale; 9: extremely good, 8: very good, 7: good, 6: slightly good, 5: average, 4: slightly bad, 3: bad, 2: very bad, 1: extremely bad), and the results are shown in Tables 4 and 5. It was determined that if the sensory evaluation results showed a bitterness level of 5 points or less and a preference level of 5 points or more, it could be used as an orally disintegrating tablet or a chewable tablet.

[0113]

[0114] [Table 4]

[0115]

[0116]

[0117] [Table 5]

[0118]

[0119]

[0120] As a result, as shown in Tables 4 and 5, when only a sweetener with short-lasting sweetness without a long-lasting sweetener, as in Comparative Example 3, was included, the bitterness could not be overcome even if the total amount of sweetener was used at least 1.5 times the weight of the main ingredient. In addition, in the case of Comparative Example 4, where the weight ratio of the total sweetener to the main ingredient exceeded 1:2, it was confirmed that although the bitterness was masked, the sweetness was too strong, resulting in low palatability.

[0121] From the results of Tables 4 and 5, it was found that in an oral pharmaceutical composition containing vonoprazan, the ratio of the sweetener to the weight of the main ingredient is preferably 1:2 or less, and that including a long-lasting sweetener capable of maintaining sweetness for a longer time than sugar in a ratio of 1:0.1 or more to the total weight of the main ingredient is effective for masking bitterness and can exhibit excellent palatability.

Claims

1. An oral pharmaceutical composition comprising a granule portion comprising vonoprazan or a pharmaceutically acceptable salt thereof and a water-insoluble polymer, wherein A composition comprising the above water-insoluble polymer in an amount of 17% to 47% by weight relative to the total weight of the granule portion.

2. A composition according to claim 1, wherein the water-insoluble polymer is one or more selected from the group consisting of methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, aminoalkyl methacrylate copolymer, dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and ethyl cellulose.

3. In claim 1, the composition further comprises a sweetener.

4. A composition according to paragraph 3, wherein the sweetener is i) included in the granule portion, ii) included in the post-mixing portion, or iii) included in both the granule portion and the post-mixing portion.

5. A composition according to claim 3, wherein the sweetener comprises i) a sweetener with a long-lasting sweetening effect or ii) a combination of a sweetener with a long-lasting sweetening effect and a sweetener with a rapid sweetening effect.

6. A composition according to claim 5, wherein the sweetener having a long-lasting sweetening effect is one or more selected from the group consisting of tomatin, neotame, sucralose, advancem, monellin, and steviol glycosides.

7. A composition according to claim 5, wherein the sweetener having a rapidly manifesting sweetening effect is one or more selected from the group consisting of sugar, acesulfame potassium, aspartame, saccharin, cyclamate, alitam, xylitol, sorbitol, maltitol, and erythritol.

8. A composition according to paragraph 3, wherein the sweetener is included in an amount of 0.2 to 2 parts by weight based on 1 part by weight of vonoprazan or a pharmaceutically acceptable salt thereof.

9. A composition according to claim 5, wherein the sweetener having a long-lasting sweetening effect is included in an amount of 0.05 or more parts by weight based on 1 part by weight of vonoprazan or a pharmaceutically acceptable salt thereof.

10. A composition according to claim 1, wherein the granule portion further comprises one or more selected from the group consisting of a diluent, a disintegrant, a flavoring agent, and a lubricant.

11. The composition of claim 1, wherein the composition further comprises a post-mixing part, said post-mixing part comprises one or more selected from the group consisting of a diluent, a disintegrant, a flavoring agent, and a lubricant.

12. The composition of claim 1, wherein the composition does not contain an organic acid.

13. A pharmaceutical preparation comprising a composition according to any one of claims 1 to 12.

14. In Paragraph 13, the above pharmaceutical preparation is an orally disintegrating tablet or a chewable tablet.

15. A pharmaceutical preparation according to Paragraph 13, wherein the total weight of the pharmaceutical preparation is 600 mg or less. 16.(a) Bonoprazan or a pharmaceutically acceptable salt thereof; or A step of forming granules by spraying a bitter-seal spray containing a water-insoluble polymer onto a mixture of vonoprazan or a pharmaceutically acceptable salt thereof and a diluent; and (b) a step of mixing the granule portion prepared in step (a) with the post-mixing portion; a method for preparing an oral pharmaceutical composition comprising, A method of manufacturing in which a water-insoluble polymer in the above composition is included in an amount of 17% to 47% by weight relative to the total weight of the granule portion.

17. A method of manufacturing according to claim 16, wherein the sweetener is i) included in the bitterness-shielding spray liquid, ii) included in the post-mixing part, or iii) included in both the bitterness-shielding spray liquid and the post-mixing part.

18. A method of manufacturing according to claim 16 or 17, wherein the post-mixing part comprises one or more selected from the group consisting of a diluent, a disintegrant, a flavoring agent, and a lubricant.

Images