Acetaminophen-containing granules

Abstract

To provide an acetaminophen-containing granule having excellent solubility in an oral cavity and provide a method for improving the oral solubility of the acetaminophen-containing granule.SOLUTION: A granule contains monosaccharide, a water-swellable material, and acetaminophen. The water-swellable material is a single water-swellable material with a swollen rate of 30% or less, or a combination of two or more water-swellable materials, the combination having a weight average swollen rate of 30% or less.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to granules containing acetaminophen and preparations containing the same, and more particularly to a rapidly dissolving preparation in the oral cavity that has excellent solubility, particularly in the oral cavity. [Background technology]

[0002] Acetaminophen is an antipyretic and analgesic ingredient listed in the Japanese Pharmacopoeia. Conventionally, it has been molded into solid oral dosage forms such as granules and tablets using various pharmaceutical additives, along with other active ingredients as needed (see, for example, Patent Documents 1 to 3). However, acetaminophen-containing granules generally have low solubility and suffer from poor swallowing comfort, such as leaving a rough feeling in the mouth after oral administration and getting stuck in the gaps between teeth or dentures. On the other hand, if fragile granules are designed and manufactured to dissolve quickly in the mouth, there is a risk that the granules will pulverize in the packaging and enter the trachea during ingestion. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Japanese Patent Application Publication No. 5-229936 [Patent Document 2] Special Publication No. 2003-509368 [Patent Document 3] Japanese Patent Application Publication No. 2018-90577 Summary of the Invention [Problem to be solved by the invention]

[0004] An object of the present invention is to improve the solubility of acetaminophen-containing granules in water, particularly in the oral cavity. Another object of the present invention is to improve the solubility of acetaminophen-containing granules in water, particularly in the oral cavity, without significantly adversely affecting their shape retention, preferably while maintaining or improving their shape retention. [Means for solving the problem]

[0005] The present inventors have conducted extensive research to solve the above problems and have found that granulating acetaminophen with a monosaccharide and a water-swellable substance having a predetermined swelling ratio to form granules improves the oral solubility without significantly affecting the shape retention of the granules. The present invention was completed based on this finding and broadly encompasses the following aspects.

[0006] (I) Preparations containing acetaminophen and their manufacturing methods (I-1) A granule containing a monosaccharide, a water-swellable substance, and acetaminophen, The granules, wherein the water-swellable substance is a single water-swellable substance having a swelling rate of 30% or less, or a combination of two or more water-swellable substances, the weight-average swelling rate of which is 30% or less. (I-2) A granule according to (I-1), wherein the monosaccharide is a combination of two or more types. (I-3) A granule according to (I-1) or (I-2), wherein the monosaccharide is a sugar alcohol. (I-4) Granules according to any one of (I-1) to (I-3), wherein the ratio of the monosaccharide to 1 part by mass of acetaminophen is 1 to 6 parts by mass. (I-5) The granule according to any one of (I-1) to (I-4), wherein the ratio of the water-swellable substance to 1 part by mass of acetaminophen is 0.05 to 1 part by mass. (I-6) The granule according to any one of (I-1) to (I-5), which is at least one selected from the group consisting of fast-dissolving granules in the oral cavity, easily soluble granules in the oral cavity, instantaneously dissolving granules in the oral cavity, and granules to be taken without water. (I-7) A preparation containing the granules according to any one of (I-1) to (I-6). (I-8) The preparation according to (I-7), which is obtained by compressing and molding the granules according to any one of (I-1) to (I-6). (I-9) A method for producing at least one type of granule selected from the group consisting of fast-dissolving granules in the oral cavity, easily soluble granules in the oral cavity, granules that instantly dissolve in the oral cavity, and granules that can be taken without water, containing a monosaccharide, a water-swellable substance, and acetaminophen, characterized in that the water-swellable substance used is a single water-swellable substance with a swelling ratio of 30% or less, or two or more water-swellable substances, so that the weight-average swelling ratio of the combined product is 30% or less.

[0007] (II) Method for improving the dissolution of acetaminophen-containing granules in the oral cavity (II-1) A method for improving the solubility in the oral cavity of a granule containing a monosaccharide, a water-swellable substance, and acetaminophen, comprising: The method for improving oral solubility is characterized in that a single water-swellable substance having a swelling rate of 30% or less is used as the water-swellable substance, or two or more water-swellable substances are used in combination so that the weight-average swelling rate is 30% or less. (II-2) The method for improving solubility in the oral cavity according to (II-1), wherein the monosaccharide is a sugar alcohol. (II-3) The method for improving solubility in the oral cavity according to (II-1) or (II-2), wherein the ratio of the monosaccharide to 1 part by mass of acetaminophen is 1 to 6 parts by mass. (II-4) A method for improving intraoral solubility according to any one of (II-1) to (II-3), wherein the ratio of the water-swellable substance to 1 part by mass of acetaminophen is 0.05 to 1 part by mass. (II-5) A method for improving oral solubility according to any one of (II-1) to (II-4), which improves oral solubility while suppressing a decrease in shape retention in a packaging material, characterized in that two or more of the monosaccharides are used in combination. [Effects of the Invention]

[0008] The granules of the present invention have excellent solubility in the oral cavity, and therefore, the granules of the present invention are unlikely to leave a rough feeling in the oral cavity after oral administration, and do not cause discomfort in the oral cavity due to insoluble granules getting into gaps in teeth, dentures, etc., and have a good feeling when taken.

[0009] Furthermore, the granules of the present invention have good shape retention, so that the granules are less likely to break down and pulverize in the packaging, and therefore there is little risk of the pulverized particles entering the trachea even when taken orally.

[0010] Furthermore, since the granules of the present invention are dissolved sufficiently and quickly in saliva in the oral cavity, they can be provided as granules that do not require water when taken.

[0011] According to the method for improving oral solubility of the present invention, it is possible to prepare the above-mentioned acetaminophen-containing granules having excellent solubility in the oral cavity. Furthermore, by using a combination of two or more monosaccharides, it is possible to prepare acetaminophen-containing granules having improved solubility in the oral cavity while suppressing a decrease in shape retention in a packaging material. DETAILED DESCRIPTION OF THE INVENTION

[0012] (I) Acetaminophen-containing preparations and their manufacturing methods The granules to which the present invention is directed (hereinafter also simply referred to as "the granules of the present invention") are granules containing a monosaccharide, a water-swellable substance, and acetaminophen.

[0013] (1) Acetaminophen (AAP) Acetaminophen is the active ingredient of the granules of the present invention and is a compound listed in the Japanese Pharmacopoeia as a drug with antipyretic and analgesic effects. Its indications include headache, earache, symptomatic neuralgia, lower back pain, muscle pain, bruise pain, sprain pain, menstrual pain, postpartum pain, cancer pain, toothache, pain after dental treatment, and pain relief from osteoarthritis; antipyretic and analgesic for acute upper respiratory tract inflammation; and antipyretic and analgesic for pediatrics.

[0014] The proportion of acetaminophen to be incorporated into the granules of the present invention is not limited, but can be appropriately set within the range of 5 to 99% by mass per 100% by mass of the granules, preferably 10 to 97% by mass, more preferably 10 to 50% by mass, for example.

[0015] (2) Monosaccharide The monosaccharides used in the granules of the present invention are basic carbohydrate substances that cannot be hydrolyzed to simpler molecules and serve as building blocks for oligosaccharides, polysaccharides, etc. Specific examples include aldoses, ketoses, pyranoses, furanoses, and sugar alcohols. Aldoses and sugar alcohols are preferred, with sugar alcohols being particularly preferred. Among sugar alcohols, alditols, which are produced by the reduction of aldoses, are preferred.

[0016] The number of carbon atoms in the monosaccharide is not particularly limited, and can usually be selected from monosaccharides with 3 to 9 carbon atoms, preferably 4 to 6 carbon atoms.

[0017] Specific examples of such monosaccharides include, but are not limited to, aldoses such as glyceraldehyde, erythrose, threose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, idose, and galactose; ketoses such as sorbose and fructose; and sugar alcohols such as glycerin, erythritol, threitol, ribitol, arabitol, xylitol, galactitol, iditol, allitol, and altritol. Preferred examples of aldoses include glucose and galactose. Preferred examples of sugar alcohols include erythritol, mannitol, sorbitol, and xylitol, and more preferably erythritol and mannitol.

[0018] The monosaccharide may be in either α-form or β-form. Furthermore, it may be in either D-form or L-form, or in either (+)-form or (-)-form, and may also be in a racemic form.

[0019] The above-mentioned monosaccharides may be used alone or in any combination of two or more. When used alone, sugar alcohols are preferred as monosaccharides, and when two or more types are combined, it is preferable to use a sugar alcohol as at least one of the monosaccharides. Furthermore, examples of monosaccharides to be combined with sugar alcohols include aldoses such as glucose and galactose. When combining sugar alcohols with aldoses, the ratio of sugar alcohol to aldose can be, for example, 0.1 to 5 parts by mass, preferably 0.5 to 2 parts by mass, of aldose per 100 parts by mass of sugar alcohol. Furthermore, oligosaccharides, polysaccharides, etc. can also be used in combination, as long as the effects of the present invention are not impaired.

[0020] The proportion of monosaccharides to be incorporated into the granules of the present invention is not limited, but can be appropriately set within the range of 0.5 to 80% by mass per 100% by mass of the granules. Examples of preferred proportions include 1 to 80% by mass, and more preferably 5 to 80% by mass. Furthermore, the proportion of monosaccharides per part by mass of acetaminophen contained in the granules is not limited, but can be within the range of 1 to 6 parts by mass. It is preferably 1 to 5 parts by mass, and more preferably 1 to 4 parts by mass.

[0021] (3) Water-swellable substances The water-swellable substance used in the granules of the present invention preferably has a swelling rate of 30% or less, more preferably 25% or less.

[0022] In the present invention, the swelling ratio (%) indicates the degree of expansion of the volume of a substance when the substance absorbs water. the law of nature, Specific details will be described in the examples below. Swelling rate of water-swellable substances Measurement method 」 Calculated using It is something that is done .

[0023] In the present invention, the lower limit of the swelling ratio of the water-swellable substance is not particularly limited as long as the effect of obtaining granules with good solubility in the oral cavity is achieved. For example, the swelling ratio may be about 3%, but from the viewpoints of the shape retention and oral solubility of the obtained granules, the swelling ratio is preferably about 5%, more preferably about 8%.

[0024] Examples of water-swellable substances with a swelling ratio of 30% or less include, but are not limited to, starch, modified starch, hydrolyzed starch, etc. Specific examples include corn starch, potato starch, wheat starch, rice starch, tapioca starch, partially pregelatinized starch, dextrin, etc. Copolyvidone, hydroxypropyl cellulose, hypromellose (degree of substitution type 2906), polyvinylpyrrolidone, etc. may also be used. Among these, in terms of the oral dissolution of the resulting granules, corn starch, partially pregelatinized starch, and dextrin are preferred, and corn starch and partially pregelatinized starch are more preferred.

[0025] The water-swellable substance may be a single water-swellable substance having a swelling rate of 30% or less, or a combination of two or more of these substances. Furthermore, in addition to a water-swellable substance having a swelling rate of 30% or less, a water-swellable substance having a swelling rate of more than 30% may be blended. The water-swellable substance having a swelling rate of more than 30% to be blended in this case is not limited, but examples thereof include a water-swellable substance having a swelling rate of more than 30% and not more than 75%. A water-swellable substance having a swelling rate of more than 30% and not more than 60% is preferred, a water-swellable substance having a swelling rate of more than 30% and not more than 50% is more preferred, and a water-swellable substance having a swelling rate of more than 30% and not more than 40% is particularly preferred. Specific examples of water-swellable substances with a swelling ratio of more than 30% and not more than 75% include carmellose, carmellose sodium, cross-polyvinylpyrrolidone, crystalline cellulose, hypromellose (degree of substitution type 2208), hypromellose (degree of substitution type 2910), methylcellulose, etc. (see JP 205-104844 A).

[0026] When a water-swellable substance with a swelling rate of more than 30% is used in combination with a water-swellable substance with a swelling rate of 30% or less, in the present invention, the water-swellable substances are blended so that the weight average swelling rate of the water-swellable substance is 30% or less, in consideration of the oral dissolution of the resulting granules.

[0027] In the present invention, the "weight average swelling ratio" refers to a value calculated as the weighted average of the swelling ratios of the respective water-swellable substances when two or more types of water-swellable substances are blended. It is also calculated as the sum of all the values ​​obtained by multiplying the swelling ratios of the respective water-swellable substances blended in the granules by their proportions as water-swellable substances.

[0028] For example, if 10 parts by mass of a water-swellable substance with a swelling rate of 15% is mixed with 5 parts by mass of a water-swellable substance with a swelling rate of 35%, the calculation is (15% × 10 parts by mass + 35% × 5 parts by mass) / (10 parts by mass + 5 parts by mass) ≒ 21.7%.

[0029] In this specification, even if two or more types of water-swellable substances are contained, if the weight-average swelling ratio of the substances is 30% or less, the two or more types of water-swellable substances may be collectively referred to simply as "water-swellable substances with a swelling ratio of 30% or less" or "water-swellable substance of the present invention."

[0030] The proportion of the water-swellable substance of the present invention to be incorporated into the granules of the present invention is not limited, but can be appropriately set within the range of 0.05 to 10% by mass per 100% by mass of the granules. Examples of preferred proportions include 1 to 10% by mass, and more preferably 1.5 to 8% by mass. Furthermore, the proportion of the water-swellable substance of the present invention (total amount in the case of a combination of two or more substances) per part by mass of acetaminophen contained in the granules is not limited, but can be within the range of 0.05 to 1 part by mass. It is preferably 0.1 to 0.8 parts by mass, and more preferably 0.1 to 0.7 parts by mass.

[0031] The ratio of the monosaccharide to the water-swellable substance of the present invention to be incorporated into the granules of the present invention is not particularly limited, and can be selected and adjusted within the range of 0.01 to 2 parts by mass per 1 part by mass of the monosaccharide. By adjusting the ratio to preferably 0.02 to 1.5 parts by mass, more preferably 0.02 to 1 part by mass, and even more preferably 0.02 to 0.2 parts by mass, the oral dissolution and shape retention of the resulting granules can be further improved.

[0032] (4) Other ingredients In addition to the acetaminophen, monosaccharide, and water-swellable substance having a swelling ratio of 30% or less, the granules of the present invention may contain other medicinal ingredients that can be used in combination with acetaminophen, such as other antipyretic analgesic anti-inflammatory agents, anti-inflammatory agents, and vitamins, as long as the effects of the present invention are not impaired.

[0033] Other antipyretic, analgesic, and anti-inflammatory agents include, for example, aniline derivatives such as phenacetin; salicylic acid derivatives such as methyl salicylate, phenyl salicylate, sodium salicylate, aspirin, aluminum aspirin, ethenzamide, and sazapyrine; pyrazolone derivatives such as isopropylantipyrine, sulpyrine, phenylbutazone, ketophenylbutazone, clofezone, antipyrine, and aminopyrine; propionic acid derivatives such as ibuprofen, ketoprofen, naproxen, loxoprofen sodium, flurbiprofen, oxacyprozin, fenoprofen calcium, tiaprofenic acid, pranoprofen, and aluminoprofen; fenbufen, diclofenac Examples of suitable antipyretics include phenylacetic acid derivatives such as thorium, amfenac sodium, alclofenac, and metiazinic acid; indoleacetic acid derivatives such as diclofenac sodium, indomethacin, indomethacin farnesyl, and sulindac; anthranilic acid derivatives such as mefenamic acid, flufenamic acid, floctafenine, and tolfenamic acid; oxicam derivatives such as piroxicam, ampiroxicam, tenoxicam, meloxicam, and lornoxicam; non-acidic (neutral, basic) antipyretic, analgesic, and anti-inflammatory agents such as benzydamine hydrochloride, epirizole (mepirizole), tiaramide hydrochloride, tinoridine hydrochloride, bucolome, and emorfazone; and COX-2 selective inhibitors such as celecoxib and rofecoxib. While not limited thereto, it is preferred that the granules of the present invention do not contain tranexamic acid.

[0034] Examples of anti-inflammatory agents include glycyrrhizinic acid, lysozyme, serrapeptase, bromelain, pronase, and salts thereof (potassium salts, hydrochlorides, etc.).

[0035] Examples of vitamins include thiamine, thiamine chloride hydrochloride, thiamine nitrate, dicethiamine hydrochloride, setotiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octotiamine, shikotiamine, thiamine disulfide, bis-ibutiamine, bis-bentiamine, prosultiamine, benfotiamine, riboflavin, riboflavin phosphate, riboflavin butyrate, riboflavin sodium phosphate, panthenol, pantethine, calcium pantothenate, sodium pantothenate, pyridoxine hydrochloride, pyridoxal phosphate, cyanocobalamin, mecobalamin, ascorbic acid, sodium ascorbate, calcium ascorbate, and hesperidin.

[0036] Furthermore, to the granules of the present invention, components such as carriers and additives, such as excipients, lubricants, colorants, antioxidants (antioxidants), disintegrants, bulking agents, refreshing agents, bases, adsorbents, fragrances, disintegration aids, coating agents, wetting agents, antifoaming agents, glossing agents, flavoring agents, suspending agents, moisture-proofing agents, preservatives, preservatives, solvents, solubilizers, synergists, attractants, solubilizers, softeners, emulsifiers, adhesives, thickeners, foaming agents, dispersants, sugar-coating agents, pH adjusters, stabilizers, surfactants, plasticizers, and buffers, can be added depending on the form and purpose of the composition.

[0037] (5) Method for producing the granules of the present invention The granules of the present invention can be produced by known granulation methods. Although not particularly limited, they can be preferably produced by wet granulation. Wet granulation is a method in which a solvent such as water and / or a lower alcohol (such as ethanol) is added to, sprayed, or sprinkled on a mixture of granulation ingredients, thereby utilizing the adhesive force of water or the like to produce granules. Such wet granulation can be carried out using known methods such as extrusion granulation, stirring granulation, fluidized bed granulation, kneading granulation, and tumbling granulation.

[0038] After granulation, the granules may be subjected to a drying treatment as appropriate. The specific drying method is not particularly limited, and any known method may be used, such as hot air drying (fluidized bed drying, tray drying, etc.), freeze drying, sun drying, etc. If hot air drying is used, the granules may be dried at about 50 to 80°C for about 1 to 24 hours.

[0039] After drying, the granules can be sieved and classified using a screen of a predetermined size, if necessary. Specifically, by using a screen with an on-size of 75 μm, 200 μm, or 355 μm, or a pass size of 500 μm, 850 μm, or 1000 μm, a granule with a particle size of 75 to 1000 μm, preferably 200 to 1000 μm, and more preferably 355 to 850 μm, can be prepared. The particle size can be measured according to the particle size measurement method described in the granules section of the 17th Edition of the Japanese Pharmacopoeia.

[0040] (6) Dosage and administration of the granules of the present invention The granules of the present invention produced by the method of the present invention described above dissolve easily in the oral cavity when taken orally, and are evaluated as having oral solubility in the present invention. Such solubility can also be described as being readily soluble in the oral cavity. In particular, granules that dissolve quickly in the oral cavity can be evaluated as having rapid oral solubility. Furthermore, granules that dissolve instantly in the oral cavity can be evaluated as having instantaneous oral solubility.

[0041] The solvent in which the granules of the present invention dissolve does not necessarily have to be water used when taking the granules. Granules that easily dissolve using body fluids such as saliva in the oral cavity as a solvent are also within the scope of the present invention. In other words, the granules of the present invention include granules that do not necessarily require water for administration, such as chewable tablets. Granules that do not require water are formulations known in the art as "granules that can be taken without water."

[0042] The daily dose (dosage) of the granules of the present invention is not particularly limited as long as it does not exceed the tolerable dose of acetaminophen. For example, the amount of acetaminophen contained in the granules can be orally administered at a dose of about 100 to 1200 mg / day depending on body weight, age, and symptoms, usually up to 4000 mg / day. It may also be administered in several divided doses per day.

[0043] The granules of the present invention are useful for mammals, particularly humans. In particular, the granules of the present invention can be suitably used for humans suffering from symptoms such as headache, earache, symptomatic neuralgia, lower back pain, muscle pain, bruise pain, sprain pain, menstrual pain, postpartum pain, cancer pain, toothache, pain after dental treatment, and osteoarthritis pain; fever reduction and pain relief for acute upper respiratory tract inflammation; and fever reduction and pain relief for pediatrics, based on the indications of acetaminophen contained therein as an active ingredient.

[0044] Furthermore, since the granules of the present invention have excellent solubility in the oral cavity, they are particularly useful for people suffering from inflammation, bleeding, etc. in the oral cavity, esophagus, stomach, and other digestive organs. Furthermore, since the granules of the present invention can be taken orally without water, they can also be conveniently used by dialysis patients who have limited fluid intake.

[0045] As described above, the granules of the present invention can be used as a pharmaceutical preparation (antipyretic analgesic) as is, and can also be used as a material for producing pharmaceutical preparations in other dosage forms. Examples of other dosage forms include capsules, pills, and tablets. Preferably, the tablets are produced by compressing the granules. Examples of tablets include chewable tablets, lozenges, and sublingual tablets that dissolve in the oral cavity. Pharmaceutical preparations in these dosage forms can be produced by conventionally known methods.

[0046] (II) Method for improving the dissolution of acetaminophen-containing granules in the oral cavity The present invention relates to a method for improving the oral solubility of acetaminophen-containing granules. This method can be carried out by using a single water-swellable substance with a swelling ratio of 30% or less for granules containing a monosaccharide, a water-swellable substance, and acetaminophen, or by using two or more water-swellable substances in combination so that the weight-average swelling ratio is 30% or less. The types and proportions of acetaminophen, monosaccharide, and water-swellable substance used here, as well as the swelling ratios and weight-average swelling ratios, are described in (I) above, and the descriptions therein are incorporated herein by reference.

[0047] In the above method, preferably, two or more monosaccharides are used in combination, thereby improving solubility in the oral cavity while suppressing a decrease in shape retention in the packaging material. When two or more monosaccharides are combined, it is preferable to use a sugar alcohol for at least one monosaccharide and an aldose for the other monosaccharide. Examples of preferred sugar alcohols include, but are not limited to, erythritol and mannitol. Examples of preferred aldoses include, but are not limited to, glucose and galactose. When a sugar alcohol and an aldose are combined, the ratio of the sugar alcohol to the aldose can be, for example, 0.1 to 5 parts by mass, preferably 0.5 to 2 parts by mass, of aldose per 100 parts by mass of sugar alcohol.

[0048] In this specification, the terms "comprise" and "contain" encompass the meanings of "consist essentially of" and "consist of." [Example]

[0049] The present invention will be specifically explained using the following experimental examples and working examples. However, the present invention is not limited to these in any way. In the following, unless otherwise specified, experiments were carried out under atmospheric pressure and room temperature conditions. Furthermore, unless otherwise specified, "%" means "% by mass" and "parts" means "parts by mass."

[0050] The methods for measuring the oral dissolution and shape retention of the granules of the present invention are as follows. <Oral solubility> Two trained panelists were asked to rinse their mouths with water, then place 0.3 g of the test granules in their mouths without water, and evaluate the dissolution sensation in the mouth. The test granules were compared with the dissolution sensation of granules (control) made of 100% acetaminophen, and the panelists evaluated the dissolution sensation of the other test granules according to the following criteria. These criteria were established by mutual agreement among the panelists so that each panelist's internal standards would be consistent. The quality of the dissolution sensation was evaluated based on the length of time required for the roughness (sensation of residual granules) to disappear in the mouth. The results of the evaluations by each panel were further mutually agreed upon among the panels, and the results were used as the final evaluation results.

[0051] [Evaluation criteria] ⊚: Much better than the control. ○: Better than the control. △: Similar to the control example. ×: Inferior to the control example.

[0052] <Shape retention> One gram of granules classified through a 42 mesh (355 μm) on 30 mesh (500 μm) sieve was placed in a centrifuge tube (outer diameter 19 (φ) × 118 (L) mm (Sumitomo Bakelite Co., Ltd.)) and subjected to vibration treatment at scale 5 for 30 seconds in a tabletop vibrator (VORTEX GENIE-2 MODEL G-560 (manufactured by SCIENTIFIC INDUSTRIES INC.)). The granules after vibration treatment were again sieved through a 42 mesh (355 μm) x 30 mesh (500 μm) sieve, and the weight of the granules remaining on the sieve was measured. The ratio of this weight (weight after vibration treatment) to the weight before vibration treatment, expressed as a percentage, was taken as the shape retention rate (%).

[0053] The swelling ratio of the water-swellable substance used in the production of granules is measured as follows. <Method for measuring swelling ratio of water-swellable substances> Eight grams of the water-swellable substance powder to be measured was placed in a sample bottle (35 mm diameter x 78 mm height), the opening of which was covered with parafilm, and the sample bottle was subjected to vibration treatment at 8 for 30 seconds in a tabletop vibrator (VORTEXGENIE-2 MOEL G-560 (manufactured by SCIENTIFIC INDUSTRIES INC.)). After the vibration treatment, the distance from the bottom of the sample bottle to the top surface of the substance (powder) enclosed therein (this was taken as the "height before swelling") was measured. Next, 3 ml of purified water and 8 g of the same water-swellable substance powder to be measured as above were added to another sample bottle, the opening of which was covered with parafilm, and the bottle was then subjected to vibration treatment under the same conditions as above. The sample bottle was then left at room temperature (25°C) for 24 hours, and the distance from the bottom of the bottle to the top of the substance enclosed therein (referred to as the "height after swelling") was measured. Based on the measurements obtained by the above method, the swelling ratio was calculated using the following formula:

[0054] [Number 1] Swelling rate (%) = [(height after swelling - height before swelling) / height before swelling] x 100

[0055] Test Example 1 (1) Preparation of acetaminophen-containing granules Granules containing acetaminophen (AAP) (Control Example, Comparative Examples 1 and 2, and Examples 1 to 6) were produced using a wet granulation method with the compositions shown in Tables 1 and 2. First, each component shown in Tables 1 and 2 was weighed and then sieved through a 30 mesh (500 μm) sieve. After sieving, the components were mixed and then wet-granulated in a mortar with an appropriate amount of water. Specifically, the components were kneaded in the mortar while adding water, and when they became soft enough that they did not crumble when lightly squeezed, they were sieved through a 30 mesh (500 μm) sieve and then dried on a tray at 70°C for 1 hour. The resulting dried product was sieved through a 22 mesh (710 μm) sieve to obtain granules.

[0056] (2) Evaluation of acetaminophen-containing granules (oral dissolution, shape retention) The acetaminophen-containing granules prepared above were evaluated for oral dissolution and shape retention according to the methods described above. The results are shown in Tables 1 and 2. [Table 1] [Table 2]

[0057] Granules containing acetaminophen (control) exhibit poor oral dissolution. This poor oral dissolution did not improve even when acetaminophen was used in combination with a water-swelling substance, partially pregelatinized starch (swelling ratio: 25%) (Comparative Example 1). However, as shown in Examples 1 to 6, it was demonstrated that granules with improved oral dissolution could be obtained by combining acetaminophen with a water-swelling substance (partially pregelatinized starch with a swelling ratio of 25%) and a monosaccharide. Furthermore, the results of Examples 3 to 6 confirmed that the combined use of two or more monosaccharides, preferably a sugar alcohol and an aldose, could produce granules with improved oral dissolution while maintaining high shape retention.

[0058] Test Example 2 Granules containing acetaminophen (Examples 7 to 9, Comparative Examples 3 to 6) were produced using the wet granulation method with the compositions shown in Table 3 in the same manner as in Test Example 1, and their oral dissolution and shape retention were evaluated. The results are also shown in Table 3. [Table 3]

[0059] As shown in Examples 7 to 9, it was revealed that granules containing water-swellable substances such as corn starch, partially pregelatinized starch, and dextrin, which have a swelling rate of 30% or less, have excellent oral solubility and shape retention.

[0060] On the other hand, granules containing ingredients with swelling rates of over 30%, such as carmellose, crystalline cellulose, low-substituted hydroxypropyl cellulose, and croscarmellose sodium, all have excellent shape retention, but their oral dissolution is poor and not entirely satisfactory.

[0061] These results confirmed that granules containing acetaminophen can be prepared by using a water-swelling substance with a swelling ratio of 30% or less in addition to a monosaccharide. Furthermore, combined with the results of Examples 1 to 6, it was confirmed that granules with good shape retention and good solubility in the oral cavity can be obtained by blending 1 to 6 parts by mass of a monosaccharide and / or 0.05 to 1 part by mass of a water-swelling substance per 1 part by mass of acetaminophen.

[0062] Test Example 3 Granules containing acetaminophen (Examples 8, 10 to 14, Comparative Examples 7 to 11) were produced using the wet granulation method with the compositions shown in Table 4 in the same manner as in Test Example 1, and their oral dissolution and shape retention were evaluated. The results are also shown in Table 4.

[0063] [Table 4]

[0064] As shown in Examples 8 and 11 to 14, it was revealed that granules containing monosaccharides generally have good oral dissolution and shape retention. Furthermore, it was revealed that, among monosaccharides, granules containing sugar alcohols (alditols) such as erythritol and mannitol have improved shape retention compared to glucose and galactose, and are excellent in both oral dissolution and shape retention. It was also confirmed that granules with better shape retention can be prepared by using a sugar alcohol (alditol) in combination with an aldose such as galactose or glucose as a monosaccharide (Example 8).

[0065] On the other hand, as shown in Comparative Examples 7 to 11, it was revealed that the granules containing oligosaccharides exhibited insufficient performance in terms of both oral dissolution and shape retention.

[0066] In the granules of the present invention, monosaccharides have smaller molecular weights than oligosaccharides and dissolve faster in water, etc., and therefore it is believed that granules containing monosaccharides have better solubility in the oral cavity than granules containing oligosaccharides.

[0067] Test Example 4 Granules containing acetaminophen (Examples 8, 15 to 21) were produced using the wet granulation method with the composition shown in Table 5 in the same manner as in Test Example 1, and their oral dissolution and shape retention were evaluated. The results are also shown in Table 5.

[0068] [Table 5]

[0069] As shown in Examples 8 and 15 to 21, it was confirmed that granules with good shape retention and better oral solubility can be prepared by increasing the ratio of monosaccharide to acetaminophen, specifically by compounding 1.5 parts by mass or more of monosaccharide per 1 part by mass of acetaminophen. Furthermore, a comparison between Examples 8 and 17 confirmed that granules with even better shape retention, with a shape retention rate of 80% or more, can be prepared by using more than 0.1 part by mass of water-swellable substance (partially pregelatinized starch), preferably 0.15 parts by mass or more, per 1 part by mass of acetaminophen.

Claims

1. A granule containing a sugar, a water-swellable substance, and acetaminophen, the carbohydrate is at least one selected from the group consisting of monosaccharides and sugar alcohols, the water-swellable substance is a single water-swellable substance having a swelling rate of 3% or more and 30% or less, or a combination of two or more water-swellable substances, the weight-average swelling rate of the combination being 3% or more and 30% or less; the water-swellable substance is at least one selected from starch, partially pregelatinized starch, and dextrin; the contents of the saccharide, the water-swellable substance, and acetaminophen in 100% by mass of the granules are ([12 / 27.7] x 100) to 80% by mass, ([0.9 / 33.1] x 100) to 8% by mass, and 10 to 50% by mass, respectively; the ratio of the carbohydrate to 1 part by mass of acetaminophen is 1 to 6 parts by mass, and the ratio of the water-swellable substance is 0.05 to 0.8 parts by mass, The granules are preparations that are dissolved in the oral cavity and taken. The granules; However, this does not apply when the granules are the following compositions (1) and (2): (1) A composition containing acetaminophen, dl-methylephedrine hydrochloride, chlorpheniramine maleate, ascorbic acid, xylitol, sucrose, aspartame, and corn starch, wherein the content of bitter components in particles of 150 μm or less is 7% by mass or less, 7.5% by mass, or 13% by mass; (2) A composition containing mannitol, sucrose, and starch, wherein the mannitol content is 10 parts by mass or more per 1 part by mass of sucrose.

2. A preparation containing the granules according to claim 1, which is dissolved in the oral cavity and taken.

3. A method for improving the solubility in the oral cavity of a granule containing a sugar, a water-swellable substance, and acetaminophen, comprising: As the water-swellable substance, a single water-swellable substance having a swelling rate of 3% or more and 30% or less is used, or two or more water-swellable substances are used in combination so that the weight-average swelling rate is 3% or more and 30% or less; the carbohydrate is at least one selected from the group consisting of monosaccharides and sugar alcohols, the water-swellable substance is at least one selected from starch, partially pregelatinized starch, and dextrin; the contents of the saccharide, the water-swellable substance, and acetaminophen in 100% by mass of the granules are ([12 / 27.7] x 100) to 80% by mass, ([0.9 / 33.1] x 100) to 8% by mass, and 10 to 50% by mass, respectively; the method for improving solubility in the oral cavity, characterized in that the ratio of the carbohydrate to 1 part by mass of acetaminophen is 1 to 6 parts by mass and the ratio of the water-swellable substance to 0.05 to 0.8 parts by mass; However, this does not apply when the granules are the following compositions (1) and (2): (1) A composition containing acetaminophen, dl-methylephedrine hydrochloride, chlorpheniramine maleate, ascorbic acid, xylitol, sucrose, aspartame, and corn starch, wherein the content of bitter components in particles of 150 μm or less is 7% by mass or less, 7.5% by mass, or 13% by mass; (2) A composition containing mannitol, sucrose, and starch, wherein the mannitol content is 10 parts by mass or more per 1 part by mass of sucrose.

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