JP2017081850A - Granulated material and oral pharmaceutical preparation containing the same as well as production method of granulated material and oral pharmaceutical preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a granulated material in which the stimulation derived from ibuprofen is inhibited and which is excellent in the elution of ibuprofen.SOLUTION: A granulated material contains (A) ibuprofen, (B) β-cyclodextrin, and (C) at least one selected from the group consisting of polyvinyl alcohol and methylcellulose.SELECTED DRAWING: None

Description

  The present invention relates to a granulated product, an oral preparation containing the same, and a method for producing the granulated product and the oral preparation.

Conventionally, ibuprofen has been used as a non-steroidal anti-inflammatory drug having antipyretic, analgesic and anti-inflammatory effects. Ibuprofen is known to be a drug with strong mucosal irritation. In addition, ibuprofen has poor water solubility, and as it is, the dissolution rate in water is slow, and there is a problem that the elution from a preparation containing this is poor.
For this reason, methods for suppressing ibuprofen mucosal irritation and methods for improving the dissolution of ibuprofen have been studied.

For example, Patent Document 1 discloses an oral solid preparation obtained by wet granulation of ibuprofen, caffeine, crystalline cellulose, and a water-soluble polymer, followed by drying. The oral solid preparation has a bitter taste and mucous membrane irritation. It is disclosed that it is excellent in concealment. However, the technique of Patent Document 1 has not fully satisfied the dissolution property of ibuprofen. Moreover, there was room for improvement also about the inhibitory property of the irritation | stimulation derived from ibuprofen.
Patent Document 2 discloses an ibuprofen-containing preparation containing ibuprofen, polyvinylpyrrolidone or copolyvidone, sodium lauryl sulfate, disodium hydrogen phosphate or smectite, and having improved ibuprofen dissolution. However, the technique of Patent Document 2 cannot sufficiently suppress the irritation derived from ibuprofen. There was also room for improvement in the dissolution of ibuprofen.
In addition, as a method for improving the dissolution property of ibuprofen, there is a method of refining a preparation containing ibuprofen. By miniaturizing, the surface area increases and the elution property of ibuprofen is enhanced. However, there is a problem that the stimulation derived from ibuprofen is strongly felt by miniaturization.

JP 2007-131561 A Japanese Patent No. 5499703

  This invention is made | formed in view of the said situation, and the irritation | stimulation derived from ibuprofen is suppressed and it aims at the granule which is excellent in the elution property of ibuprofen, and a tablet containing this.

As a result of intensive studies, the present inventors have found that the following granulated product can solve the above problems.
That is, the present invention has the following configuration.
[1] A granulated product containing ibuprofen (A), β-cyclodextrin (B), and at least one selected from the group consisting of polyvinyl alcohol and methylcellulose (C).
[2] The granulated product according to [1], wherein a mass ratio represented by the component (B) / the component (A) is 0.4 or more.
[3] The granulated product according to [1] or [2], wherein a mass ratio represented by the component (C) / the component (A) is 0.03 or more.
[4] An oral preparation containing the granulated product according to any one of [1] to [3].
[5] The oral preparation according to [4], wherein the dosage form of the oral preparation is a granule, tablet, pill, gummi or jelly.
[6] Furthermore, it contains at least one (D) selected from the group consisting of l-menthol, dl-menthol, d-camphor and dl-camphor, and is represented by the component (D) / the component (A). The oral preparation according to [5], wherein the mass ratio is 0.003 or more.
[7] The oral preparation according to [5] or [6], wherein the dosage form is a tablet, and the tablet is a chewable tablet or an orally disintegrating tablet.
[8] A method for producing a granulated product according to any one of [1] to [3], wherein the component (A), the component (B) and the component are obtained by a melt granulation method or a wet granulation method. (C) The manufacturing method of the granulated material which granulates the raw material containing a component and obtains a granulated material.
[9] A method for producing an oral preparation comprising a step of obtaining a granulated product by the method for producing a granulated product according to [8], and a step of blending the granulated product obtained in the step.

  The granulated product of the present invention is excellent in ibuprofen-derived irritation-suppressing properties and ibuprofen elution.

It is a ¹ H-NMR chart of β-cyclodextrin. 3 is a ¹ H-NMR chart of the granulated product of Example 3. FIG.

(Granulated product)
The granulated product of the present invention comprises ibuprofen (component (A)), β-cyclodextrin (component (B)), at least one selected from the group consisting of polyvinyl alcohol and methylcellulose (component (C)), Containing. The granulated product of the present invention is a group of granulated particles containing the components (A) to (C).
The granulated product of the present invention is suitable as an oral preparation because it is excellent in suppressing the irritation derived from the component (A) and is excellent in the dissolution property of the component (A). Moreover, since it is excellent in caking suppression property, it is excellent in the handleability at the time of mix | blending with storage or an oral formulation. Furthermore, since it is easy to dissolve in the oral cavity and a good texture with reduced roughness is obtained, it is suitably used as a raw material for chewable tablets or orally disintegrating tablets that are taken without water, for example.

Although the average particle diameter of the granulated product of the present invention is not particularly limited, for example, 20 to 2000 μm is preferable, and 50 to 1500 μm is more preferable. It becomes easy to suppress that a granulated material aggregates that the average particle diameter of a granulated material is more than the said lower limit. Moreover, the solubility in the oral cavity of a granulated material does not become high too much, and the irritation | stimulation suppression effect becomes high. When the average particle size of the granulated product is not more than the above upper limit, the solubility of the granulated product is enhanced and the immediate effect is easily enhanced.
In this specification, an average particle diameter means the volume average particle diameter measured by the apparatus (For example, LS13320 by Beckman Coulter, Inc.) by the laser diffraction and a scattering method.

The bulk density of the granulated product of the present invention is preferably 0.25 to 0.8 g / cm ³ , and more preferably 0.35 to 0.7 g / cm ³ . If the bulk density of the granulated product is 0.25 g / cm ³ or more, filling and the like when blended into an oral preparation are facilitated, and troubles such as poor filling are less likely to occur, and 0.8 g / cm ³ or less. For example, active ingredients are less likely to be unevenly distributed in oral preparations.
In this specification, the bulk density is a value measured in accordance with JIS K 3362.

<(A) component>
(A) A component is ibuprofen. Ibuprofen is a known non-steroidal anti-inflammatory drug, and is a drug formulated as an active ingredient in antipyretic analgesics and cold medicines.
10-70 mass% is preferable with respect to the total mass of a granulated material, and, as for content of (A) component, 15-65 mass% is preferable, and 20-60 mass% is more preferable. It becomes easy to mix | blend (A) component in a granulated material so that it may become a desired dose as content of (A) component is more than the said lower limit. Moreover, the irritation | stimulation derived from (A) component becomes easy to be suppressed as content of (A) component is below the said upper limit.
(A) The dosage per component is preferably 30 to 300 mg, preferably 40 to 250 mg, more preferably 50 to 200 mg, and particularly preferably 65 to 160 mg. When the dose per component (A) is equal to or more than the lower limit, the antipyretic analgesic effect is improved. When the dose per component (A) is equal to or less than the upper limit, stimulation derived from the component (A) is easily suppressed.

<(B) component>
The component (B) is β-cyclodextrin. By containing the component (B) together with the component (C) described below, the granulated product of the present invention suppresses irritation derived from the component (A) and enhances the elution of the component (A). Furthermore, the solubility of the granulated product is enhanced, and it becomes easy to obtain a granulated product excellent in texture with reduced roughness.
As cyclodextrins, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and the like are known, and the sizes of pores inside the cyclic structure in the molecule are different. In this invention, by using (beta) -cyclodextrin ((B) component), the irritation | stimulation derived from (A) component is suppressed and the elution property of (A) component is improved. This is presumably because the component (B) is likely to interact with the component (A) compared to α-cyclodextrin and the like.

Cyclodextrin is known to have a peak of H3 and H5 inside the cyclic structure shifted to the high magnetic field side in ¹ H-NMR measurement when other molecules are included inside the cyclic structure (for example, Wood, DJ, JACS, 1977, 99, p. 1735).
FIG. 1 shows a ¹ H-NMR chart of β-cyclodextrin, and FIG. 2 shows a ¹ H-NMR chart of the granulated product of Example 3.
As shown in the ¹ H-NMR chart of FIG. 2, the peaks of H3 and H5 of β-cyclodextrin in the granulated product of the present invention are compared with the peaks of H3 and H5 of β-cyclodextrin alone in FIG. Shifted to the high magnetic field side. From this, in the granulated product of the present invention, it is considered that at least a part of the component (A) is included in the component (B).
In the ¹ H-NMR chart, the measurement object (β-cyclodextrin or granulated product of Example 3) was dissolved in heavy water (sample concentration 30% by mass), and this was converted to ¹ H-NMR (JEOL). It is obtained by measuring with JNM-LA300 FT NMR SYSTEM.

  (B) As for content of a component, 10-80 mass% is preferable with respect to the gross mass of a granulated material, 20-70 mass% is preferable, and 25-70 mass% is more preferable. It becomes easy to suppress the irritation | stimulation derived from (A) component as content of (B) component is more than the said lower limit. Moreover, it becomes easy to improve the elution property of (A) component. Furthermore, it becomes easy to obtain a granulated product in which consolidation is suppressed. In addition, it becomes easy to improve the solubility of the granulated product, and a good texture can be easily obtained. When the content of the component (B) is not more than the above upper limit, the content of the component (B) does not become too high, and it becomes easy to adjust the content of the component (A) to a range where a desired dose can be obtained. .

<(C) component>
The component (C) is at least one selected from the group consisting of polyvinyl alcohol and methylcellulose. By containing the component (C) together with the component (B) described above, the granulated product of the present invention can suppress irritation derived from the component (A) and enhance the elution of the component (A). Moreover, the caking suppression property of a granulated material is improved. Furthermore, the solubility of the granulated product is enhanced, and a good texture is easily obtained when taken.
Although it does not specifically limit as polyvinyl alcohol, For example, the thing of a weight average molecular weight of 1,000-5,000,000 g / mol is preferable, The thing of 2,000-3,000,000 g / mol is more preferable, The thing of 3,000-1,000,000 g / mol is further more preferable. When the weight average molecular weight of the polyvinyl alcohol is not less than the lower limit, the irritation derived from the component (A) is easily suppressed, and the elution property of the component (A) is easily improved. When the weight average molecular weight of the polyvinyl alcohol is not more than the above upper limit value, the handleability of the polyvinyl alcohol becomes good and it becomes easy to produce a granulated product. Moreover, as a saponification degree (mol%) which shows the ratio of the hydroxyl group with respect to the total amount of the hydroxyl group and acetic acid group of polyvinyl alcohol, the thing of 80.0-95.0 mol% is preferable, and 85.0-90.0 mol% More preferably, 86.5-89.0 mol% is more preferable. When the degree of saponification of polyvinyl alcohol is not less than the above lower limit, the coating strength is increased and the stimulus suppressing effect is enhanced. When the degree of saponification of polyvinyl alcohol is less than or equal to the above upper limit, the solubility of the granulated product is enhanced and the immediate effect is easily enhanced.
In addition, the methyl cellulose is not particularly limited, but for example, a weight average molecular weight of 1,000 to 5,000,000 g / mol is preferable, and that of 2,000 to 3,000,000 g / mol is more preferable. More preferably, 3,000 to 1,000,000 g / mol. When the weight average molecular weight of methyl cellulose is not less than the lower limit, the irritation derived from the component (A) is likely to be suppressed, and the elution property of the component (A) is easily improved. When the weight average molecular weight of methyl cellulose is not more than the above upper limit value, the handleability of methyl cellulose is improved and it becomes easy to produce a granulated product.
In addition, the weight average molecular weight in this invention is a value measured by GPC-MALLS system.
As the component (C), any one of them may be used alone, or two or more may be used in combination.

  The content of the component (C) is preferably 0.01 to 40% by mass, more preferably 0.1 to 35% by mass, and further preferably 0.3 to 30% by mass with respect to the total mass of the granulated product. 0.5 to 25% by mass is particularly preferable. It becomes easy to suppress the irritation | stimulation derived from (A) component as content of (C) component is more than the said lower limit. Moreover, it becomes easy to improve the elution property of (A) component. Furthermore, it becomes easy to obtain a granulated product in which consolidation is suppressed. Moreover, it becomes easy to improve the solubility of a granulated material, and the rough feeling at the time of taking is suppressed, and it becomes easy to obtain a favorable food texture. When the content of the component (C) is not more than the above upper limit, the content of the component (C) does not become too high, and it becomes easy to adjust the content of the component (A) to a range where a desired dose can be obtained. .

  The mass ratio represented by the component (B) / the component (A) [the mass ratio of the content of the component (B) to the content of the component (A), hereinafter also referred to as “B / A ratio”] is 0. .4 or more is preferable, 0.7 or more is more preferable, 1.2 or more is further preferable, and 1.5 or more is particularly preferable. When the B / A ratio is equal to or higher than the lower limit value, stimulation derived from the component (A) is easily suppressed, and the elution property of the component (A) is easily increased. Further, the B / A ratio is preferably 8 or less, more preferably 5.5 or less, further preferably 3.1 or less, and particularly preferably 2.4 or less. When the B / A ratio is less than or equal to the above upper limit, the solubility of the granulated product is enhanced, and a rough texture is suppressed when taken, making it easy to obtain a good texture. Furthermore, it becomes easy to obtain a granulated product in which consolidation is suppressed. In addition, when the granulated product of the present invention is blended with a tablet, the tablet can be made small, and the ingestion is improved. The B / A ratio is preferably 0.4 to 8, more preferably 0.7 to 5.5, still more preferably 1.2 to 3.1, and particularly preferably 1.5 to 2.4.

The mass ratio represented by the component (C) / the component (A) [the mass ratio of the content of the component (C) to the content of the component (A), hereinafter also referred to as “C / A ratio”] is 0 0.03 or more is preferable, 0.07 or more is more preferable, 0.15 or more is further preferable, and 0.25 or more is particularly preferable. When the C / A ratio is equal to or higher than the lower limit, irritation derived from the component (A) is easily suppressed, and the elution property of the component (A) is easily increased. In addition, the solubility of the granulated product is enhanced, and a good texture is easily obtained. The C / A ratio is preferably 2.0 or less, more preferably 1.5 or less, still more preferably 0.8 or less, and particularly preferably 0.65 or less. When the C / A ratio is less than or equal to the above upper limit value, the unpleasant taste peculiar to the polymer compound is easily suppressed, and good dosing properties are easily obtained. Moreover, it becomes easy to obtain a granulated product that is excellent in suppression of consolidation, in particular, suppression of consolidation due to moisture absorption. The C / A ratio is preferably 0.03 to 2.0, more preferably 0.07 to 1.5, still more preferably 0.15 to 0.8, and particularly preferably 0.25 to 0.65.
The total content of the components (A) to (C) in the granulated product is 100% by mass or less.

The granulated product of the present invention may contain optional components other than the components (A) to (C). Examples of the optional component include excipients, binders, disintegrants, sweeteners, preservatives, fragrances, pigments, lubricants, and the like.
Examples of the excipient include lactose, corn starch, crystalline cellulose, potato starch; sugar alcohols such as mannitol, erythritol, xylitol, sorbitol, palatinit, and lactitol; talc and the like.
Examples of the binder include hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, hydroxyethylcellulose, gum arabic, pregelatinized starch, sodium alginate, carboxyvinyl polymer, agar, honey and the like.
Examples of the disintegrant include crospovidone, croscarmellose sodium, carmellose calcium, carboxymethyl starch sodium, and low-substituted hydroxypropylcellulose.
Examples of the sweetening agent include sucrose, fructose, aspartame, acesulfame potassium, thaumatin, stevia, purified white sugar, saccharin, glycyrrhizin and the like.
Examples of the preservative include parabens, paraoxybenzoic acid ester, sodium benzoate and the like.
Examples of the fragrances include limonene, orange flavor, lychee flavor, lemon flavor, lime flavor, strawberry flavor, pineapple flavor, peach flavor, mint flavor, and grapefruit flavor.
Examples of the pigment include caramel, carmine, carotene solution, β-carotene, copper chlorophyll, and copper chlorophyllin sodium.
Examples of the lubricant include magnesium stearate, calcium stearate, sodium stearyl fumarate, talc and the like.
Any one of these additives may be used alone, or two or more thereof may be used in combination.

(Oral formulation)
The oral preparation of the present invention contains the above granulated product. In the oral preparation of the present invention, the granulated product is contained in the form of a granulated product without being dissolved or melted.
By including the granulated product, the oral preparation of the present invention suppresses irritation derived from the component (A) and enhances the elution of the component (A). Moreover, it becomes easy to obtain the favorable food texture which was excellent in the solubility of the granulated material and the rough feeling was suppressed.
Although it does not specifically limit as an oral formulation, For example, a granular agent (a granule, a powder etc.), a tablet (a chewable tablet, an orally disintegrating tablet, an effervescent tablet, etc.), a pill, a gummy agent, and a jelly agent are preferable. From the viewpoint of easily enjoying the effects of the present invention, tablets are preferable, chewable tablets and orally disintegrating tablets are more preferable, and chewable tablets and orally disintegrating tablets to be taken without water are more preferable.

  The content of the granulated product in the oral preparation is not particularly limited. For example, when the oral preparation is a granule, it is preferably 30% by mass or more, and preferably 40% by mass or more, based on the total mass of the granule. 50 mass% or more is preferable. It becomes easy to adjust content of (A) component in an oral formulation in the range from which a desired dose is obtained as content of a granulated material is more than the said lower limit. Further, the content of the granulated product may be 100% by mass, preferably 98% by mass or less, more preferably 95% by mass or less, and still more preferably 90% by mass or less, based on the total mass of the granule. . When the content of the granulated product is not more than the above upper limit value, the degree of freedom in blending other components is increased.

  When the oral preparation is a tablet or pill, the content of the granulated product is not particularly limited, but for example, 5% by mass or more is preferable and 10% by mass or more is preferable with respect to the total mass of the tablet or pill. It becomes easy to adjust content of (A) component in a tablet or a pill to the range from which a desired dose is obtained as content of a granulated material is more than the said lower limit. The content of the granulated product may be 100% by mass, preferably 90% by mass or less, more preferably 80% by mass or less, and 70% by mass or less based on the total mass of the tablet or pill. Further preferred. When the content of the granulated product is not more than the above upper limit value, the degree of freedom in blending other components is increased.

  When the oral preparation is a gummy agent, the content of the granulated product is not particularly limited, but is preferably 0.1 to 50% by mass, more preferably 1 to 30% by mass, for example, with respect to the total mass of the gummy agent. 3 to 20% by mass is more preferable. It becomes easy to adjust content of the (A) component in a gummi preparation in the range from which a desired dose is obtained as content of a granulated material is more than the said lower limit. Moreover, it becomes easy to obtain the gummi agent with which the irritation | stimulation derived from (A) component was suppressed as content of a granulated material is below the said upper limit. Moreover, it becomes easy to obtain the gummi agent which is suppressed in a rough feeling and is excellent in food texture.

  When the oral preparation is a jelly agent, the content of the granulated product is not particularly limited. For example, 0.001 to 20% by mass is preferable with respect to the total mass of the jelly agent, and 0.005 to 10% by mass is preferable. More preferably, 0.01-5 mass% is further more preferable, and 0.1-3 mass% is especially preferable. It becomes easy to adjust content of (A) component in a jelly agent in the range from which a desired dose is obtained as content of a granulated material is more than the said lower limit. Moreover, it becomes easy to obtain the jelly agent by which the irritation | stimulation derived from (A) component was suppressed as content of a granulated material is below the said upper limit. Moreover, it becomes easy to obtain the jelly agent which suppresses a rough feeling and is excellent in texture.

  The oral preparation of this invention may contain arbitrary components other than the said granulated material. The oral preparation of the present invention preferably contains the following component (D).

<(D) component>
The oral preparation of the present invention can contain at least one (component (D)) selected from the group consisting of 1-menthol, dl-menthol, d-camphor and dl-camphor.
When the oral preparation contains the component (D), the stimulation derived from the component (A) is further suppressed.
Although content of (D) component is adjusted suitably, 0.001-10 mass% is preferable with respect to the total mass of an oral formulation, for example, 0.005-8 mass% is more preferable, 0.01 -5% by mass is more preferable, and 0.01-3% by mass is particularly preferable. When the content of the component (D) is in the above-described preferable range, irritation derived from the component (A) is suppressed, and an oral preparation having excellent dosing properties is easily obtained.
The mass ratio represented by the component (D) / the component (A) [the mass ratio of the content of the component (D) to the content of the component (A), hereinafter also referred to as “D / A ratio”] is 0. 0.003 or more is preferable, 0.005 or more is more preferable, 0.008 or more is further preferable, 0.01 or more is particularly preferable, and 0.02 or more is most preferable. When the D / A ratio is equal to or higher than the lower limit value, the stimulus suppressing effect is easily enhanced. The D / A ratio is preferably 0.5 or less, more preferably 0.3 or less, further preferably 0.2 or less, particularly preferably 0.18 or less, and most preferably 0.15 or less. When the D / A ratio is less than or equal to the above upper limit, an oral preparation having excellent dosing properties can be easily obtained. The D / A ratio is preferably 0.003 to 0.5, more preferably 0.005 to 0.3, further preferably 0.008 to 0.2, particularly preferably 0.01 to 0.18, and 0 0.02-0.15 is most preferred.

The oral preparation of this invention may contain arbitrary components other than the said (D) component. Examples of the optional component include additives that are usually blended in oral preparations. For example, oral preparations of the invention include granules (granulates, powders, etc.), tablets (chewable tablets, orally disintegrating tablets, effervescent tablets, etc.) ), Pills, and the like, excipients, binders, disintegrants, sweeteners, preservatives, fragrances, pigments, lubricants and the like can be mentioned. Examples of these additives include the same excipients, binders, disintegrants, sweeteners, preservatives, fragrances, pigments, and lubricants as optional components of the granulated product.
Any one of these additives may be used alone, or two or more thereof may be used in combination.
Moreover, these additives may be mix | blended as a granule containing any 1 type (s) or 2 or more types.

Examples of additives that are added when the oral preparation of the present invention is a gummi, jelly, paste, etc. include, for example, pH adjusters, sweeteners, thickeners, preservatives / preservatives, stabilizers, etc. Is mentioned.
Examples of the pH adjuster include succinic acid, acetic acid, ammonium acetate, tartaric acid, sodium tartrate, borax, lactic acid, calcium lactate hydrate, sodium lactate, malic acid and the like.
Examples of the sweetener include sucrose, liquid sugar, fructose, fructose glucose liquid, glucose fructose liquid sugar, reduced maltose starch syrup, brown sugar, high fructose liquid sugar, glucose, powdered reduced maltose starch syrup, starch syrup, high glucose syrup, lactose Sucrose, purified sucrose, purified sucrose spherical granules, honey, purified honey, simple syrup, erythritol, xylitol, D-sorbitol, D-sorbitol, maltitol, maltitol, maltose, D-mannitol, aspartame, acesulfame potassium, Amacha extract, licorice extract, saccharin, saccharin sodium, sucralose, stevia extract, neotame, thaumatin, glycine, dipotassium glycyrrhizinate, disodium glycyrrhizinate, trisodium glycyrrhizinate, monoammonium glycyrrhizinate, licorice, etc. It is below.

Examples of the thickener include natural water-soluble polymers such as agar, gelatin, pectin, carrageenan, locust bean gum, gellan gum, xanthan gum, guar gum, pullulan, gum arabic, glucomannan, curdlan, alginic acid, and alginates; polyvinyl Synthetic water-soluble polymers such as alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl cellulose, polyacrylic acid, polyacrylic acid partial neutralized product, polyacrylic acid salt, and polyacrylic acid partial neutralized product salt.
The content of the thickening agent is appropriately adjusted according to the dosage form of the oral preparation and the type of the thickening agent, but is 0.01 to 15% by mass relative to the total mass of the gummi or jelly agent, for example. Is preferable, and 0.1-10 mass% is more preferable.
Examples of preservatives and preservatives include benzoic acid, sodium benzoate, ethanol, sodium edetate, dried sodium sulfite, agar, citric acid, sodium citrate, glycerin, salicylic acid, sodium salicylate, phenyl salicylate, dibutylhydroxytoluene, D-sorbitol, sorbic acid, potassium sorbate, sodium dehydroacetate, isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, ethyl paraoxybenzoate, butyl paraoxybenzoate, propyl paraoxybenzoate, methyl paraoxybenzoate, propylene glycol, l- Mentor, eucalyptus oil and the like.
As stabilizers, L-ascorbic acid stearate, sodium L-ascorbate, sodium L-aspartate, aminoethylsulfonic acid, DL-alanine, sodium bisulfite, sodium sulfite, L-arginine, sodium alginate, alginic acid Propylene glycol, albumin, sulfur, inositol, edetate calcium disodium, erythorbic acid, sodium sorbate, calcium chloride, sodium chloride, potassium chloride, magnesium chloride, cysteine hydrochloride, cocoa butter, fructose, carboxyvinyl polymer, carmellose calcium, Carmellose sodium, hydrous silicon dioxide, dry sodium carbonate, xanthan gum, xylitol, calcium citrate, glycerin fatty acid ester, glycy Disodium ritinate, light anhydrous silicic acid, crystalline cellulose, tocopherol acetate, sodium acetate, dextrin, sucrose fatty acid ester, calcium hydroxide, purified gelatin, purified soybean lecithin, sorbitan sesquioleate, cetanol, sorbitan fatty acid ester, D- Sorbitol solution, soybean oil unsaponifiable matter, dextran, natural vitamin E, tocopherol, d-δ-tocopherol, nicotinamide, lactose, concentrated glycerin, calcium pantothenate, microcrystalline cellulose, hydroxypropylcellulose, sodium pyrosulfite, butylhydroxy Anisole, glucose, sodium fumarate, bentonite, propyl gallate, partially neutralized polyacrylic acid, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropi Examples include lenglycol, polysorbate, polyvinylpyrrolidone, macrogol, maltose, D-mannitol, anhydrous sodium pyrophosphate, sodium metaphosphate, methylcellulose, glyceryl monostearate, medicinal charcoal, sodium lauryl sulfate, and egg white albumin.
Any one of these additives may be used alone, or two or more thereof may be used in combination.
Moreover, these additives may be mix | blended as a granule containing any 1 type (s) or 2 or more types.

(Production method)
<Method for producing granulated product>
The granulated product of the present invention is produced by granulating the component (A), the component (B) and the component (C).
A known granulation method can be applied as the granulation method. Examples of the granulation method include a melt granulation method and a wet granulation method.
The melt granulation method is generally a method in which a drug is melted by heating or the like to form a liquid and then cooled and solidified for granulation.
The wet granulation method is a method of granulating by adding a liquid such as water, and examples thereof include an extrusion granulation method, a fluidized bed granulation method, a stirring granulation method, and a rolling granulation method.
Among these granulation methods, it is possible to obtain a granulated product having excellent caking suppression, a point to obtain a granulated product in which irritation derived from the component (A) is suppressed, and a good texture with reduced roughness. The melt granulation method is preferred from the viewpoint of obtaining the resulting granulated product.

[Melt granulation method]
As the melt granulation method, the (A) component melting step to make a liquid, the (A) component, the (B) component and the (C) component mixing step to obtain a mixture, And a granulation step of granulating by cooling the mixture.
In the melting step, the component (A) is heated and melted to form a liquid. The heating temperature is preferably a temperature equal to or higher than the melting point of the component (A), for example, 80 ° C. or higher.
In the said mixing process, (A) component, (B) component, and (C) component are mixed, and a mixture is obtained. The order of mixing the component (A), the component (B), and the component (C) is not particularly limited, but the irritation derived from the component (A) is more easily suppressed, and the elution property of the component (A) It is preferable to mix (B) component after mixing (A) component and (C) component from the point which becomes easy to raise more. The mixing of the component (A) with the component (B) and the component (C) may be performed before the component (A) is heated and melted, or the component (A) is heated and melted to form a liquid. It may be done later. (A) Component (A) After mixing (A) component and (C) component from the point that the irritation | stimulation derived from (A) component becomes easy to be suppressed, and the elution property of (A) component becomes easier to improve. It is preferable to heat and melt to form a liquid, and then mix the component (B).
In the granulation step, the mixture of component (A), component (B) and component (C) is cooled to prepare a granulated product. The granulated product may be prepared by cooling while spraying the mixture as droplets with a nozzle or the like, or may be prepared by cooling the mixture to form a solid. From the viewpoint of excellent productivity, it is preferable to prepare by cooling the mixture to form a solid. The cooling temperature is not particularly limited as long as the mixture becomes a solid temperature, but room temperature (for example, 15 to 35 ° C.) is preferable from the viewpoint of excellent productivity.
In the melt granulation method, for example, a granulated product having an average particle diameter of 50 to 300 μm, preferably an average particle diameter of 100 to 200 μm is produced. The melt granulation method is easy to obtain a granulated product having a small average particle diameter, can produce a granulated product having a good mouthfeel and an excellent texture, and has excellent handling properties because adhesion to a production apparatus is suppressed. It is preferable to the extrusion granulation method described later in that a granulated product can be produced.

[Extrusion granulation method]
Among the wet granulation methods, for example, as an extrusion granulation method, there are a kneaded material preparing step for preparing a kneaded material containing the component (A), the component (B) and the component (C), and the kneaded material in an extruder. And a granulation step of preparing an extrudate by feeding and preparing a granulated product from the extrudate.
In the kneaded product preparation step, a known kneader is charged with (A) component, (B) component, (C) component and, if necessary, additives such as excipients to form a mixture. An operation of adding components and kneading is performed. The order in which the components (A), (B), and (C) are charged is arbitrary, and the components (A), (B), and (C) may be charged in any order. Components or three components may be added simultaneously. The addition amount of the liquid component is appropriately adjusted, and is, for example, 10 to 20% by mass with respect to the total mass of the mixture. Moreover, as said liquid component, water is preferable from the point which can improve interaction with (A) component and (B) component more. When water is used as the liquid component, it becomes easy to obtain a granulated product in which irritation derived from the component (A) is suppressed and the elution of the component (A) is enhanced.
In the granulation step, the kneaded product is put into a known extrusion granulator, pressure is applied by a screw, plunger, roller, etc., and the kneaded product is extruded from a screen die having arbitrary holes to prepare an extrudate. However, the operation of cutting the extrudate with a cutter or the like to obtain a granulated product is performed.
In the extrusion granulation method, after the granulation step, a drying step for drying the granulated product, and a granulating step for adjusting the average particle size and particle size distribution of the granulated product may be provided. In the drying step, an operation of drying the granulated product to adjust the moisture content of the granulated product is performed. In this drying step, the water content of the granulated product is, for example, 0 to 5% by mass with respect to the total mass of the granulated product. In the sizing step, an operation of adjusting the average particle size and particle size distribution of the granulated product is performed by pulverization, sieving or the like.
In the extrusion granulation method, for example, a granulated product having an average particle diameter of 500 to 2000 μm, preferably an average particle diameter of 750 to 1500 μm is produced.

<Method for producing oral preparation>
Although the oral formulation of this invention is not specifically limited, The process of obtaining a granulated material with the manufacturing method of the said granulated material, and the process of mix | blending the granulated material obtained at the said process are provided.
The oral preparation of this invention can be manufactured by a conventional method according to a dosage form.
For example, when the oral preparation of the present invention is a granule (granule, powder, etc.), the granulated product can be used as a granule as it is. Moreover, the mixture which mixed the said granulated material, the granule containing the other arbitrary component or another arbitrary component, etc. may be prepared, and it is good also as a granule. The granulated product and / or other optional components may be coated, or may be subjected to a granulating operation or a sizing operation.
If the oral preparation of the present invention is a tablet, the granulated product may be tableted as it is to form a tablet, the granulated product and other optional ingredients or granules containing other optional ingredients, etc. A mixture may be prepared and tableted by tableting. The granulated product and / or other optional components may be coated, or may be subjected to a granulating operation or a sizing operation. Tableting can be performed using a known tableting machine. The tableting machine is not particularly limited, and examples thereof include a rotary tableting machine. For example, the product name “LIBRA” manufactured by Kikusui Seisakusho Co., Ltd. -AP-MS type ". The tableting pressure is adjusted as appropriate, but for example, it is preferably adjusted so that the tablet has a tensile strength of 75 to 250 N / cm ² .
When the oral preparation of the present invention is a gummi preparation or a jelly preparation, a liquid product is prepared by warm-mixing water and a thickener, and an optional component is added and dissolved in the liquid product. Is cooled to below the melting point of the component (A), the above granulated product and the remaining optional components are added and mixed, and this mixture is placed in a mold and cooled to form a gummy agent or jelly agent. .

As described above, since the granulated product of the present invention contains the component (A), the component (B) and the component (C), irritation derived from the component (A) is suppressed, and the component (A) Excellent elution performance. Moreover, since it is excellent in caking suppression property, it is excellent in the handleability at the time of mix | blending with storage or an oral formulation. Furthermore, it is easy to dissolve in the oral cavity, and a good texture with reduced roughness is obtained.
Since the oral preparation of this invention contains the said granulated material, the irritation | stimulation derived from (A) component is suppressed and it is excellent in the elution property of (A) component. Furthermore, it is easy to dissolve in the oral cavity, and a good texture with reduced roughness is obtained. For example, even when the dosage form of an oral preparation is a chewable tablet or an orally disintegrating tablet that can be taken without water, the effects of the present invention can be fully enjoyed.

The present invention has, for example, the following aspects.
[1] A granulated product containing ibuprofen (A), β-cyclodextrin (B), and at least one selected from the group consisting of polyvinyl alcohol and methylcellulose (C).
[2] The granulated product according to [1], wherein a mass ratio represented by the component (B) / the component (A) is 0.4 or more.
[3] The granulated product according to [1] or [2], wherein a mass ratio represented by the component (C) / the component (A) is 0.03 or more.
[4] The content of (A) is 10 to 70% by mass with respect to the total mass of the granulated product, and the content of the component (B) is based on the total mass of the granulated product. It is 10 to 80% by mass, and the content of the component (C) is 0.01 to 40% by mass with respect to the total mass of the granulated product, according to any one of [1] to [3]. Granulated material. However, the total content of the component (A), the component (B) and the component (C) does not exceed 100% by mass.
[5] An oral preparation containing the granulated product according to any one of [1] to [4].
[6] The oral preparation of [5], wherein the dosage form is a granule, tablet, pill, gummi or jelly.
[7] The oral preparation according to [6], further comprising at least one (D) selected from the group consisting of l-menthol, dl-menthol, d-camphor and dl-camphor.
[8] The oral preparation according to [7], wherein a mass ratio represented by the component (D) / the component (A) is 0.003 or more.
[9] The oral preparation according to any one of [6] to [8], wherein the dosage form is a tablet, and the tablet is a chewable tablet or an orally disintegrating tablet.
[10] The oral preparation of [9], wherein the chewable tablet or orally disintegrating tablet is to be taken without water.
[11] The oral form according to any one of [5] to [8], wherein the dosage form is a granule and contains the granulated product in an amount of 30 to 100% by mass with respect to the total mass of the granule. Formulation.
[12] Any of [5] to [10], wherein the dosage form is a tablet or pill, and the granulated product is contained in an amount of 5 to 100% by mass based on the total mass of the tablet or pill. Oral preparations described in 1.
[13] The formulation according to any one of [5] to [8], wherein the dosage form is a gummi agent, and the granulated product is contained in an amount of 0.1 to 50% by mass with respect to the total mass of the gummi agent. Oral formulation.
[14] The formulation according to any one of [5] to [8], wherein the dosage form is a jelly agent and the granulated product is contained in an amount of 0.001 to 20% by mass relative to the total mass of the jelly agent. Oral formulation.
[15] A method for producing a granulated product according to any one of [1] to [4],
The manufacturing method of the granulated material which granulates the raw material containing the said (A) component, the said (B) component, and the said (C) component by a melt granulation method or a wet granulation method, and obtains a granulated material.
[16] The melt granulation method includes a melting step of melting the component (A) to form a liquid, and a mixing step of mixing the components (A), (B), and (C) to obtain a mixture. And a granulation step of granulating the mixture by cooling the mixture, [15].
[17] The wet granulation method is an extrusion granulation method, and the extrusion granulation method is a kneaded material for preparing a kneaded material containing the component (A), the component (B), and the component (C). An operation of adding a liquid component to the mixture containing the component (A), the component (B), and the component (C) in the kneaded product preparing step, and kneading the mixture. The manufacturing method of the granulated material of description.
[18] An oral preparation comprising a step of obtaining a granulated product by the method for producing a granulated product according to any one of [15] to [17], and a step of blending the granulated product obtained in the step Production method.

EXAMPLES Hereinafter, although an Example is shown and this invention is demonstrated in detail, this invention is not limited by the following description.
The raw materials used in this example are as follows.

(Raw materials used)
<(A) component>
・ Ibuprofen, manufactured by BASF.

<(B) component>
-Β-cyclodextrin, manufactured by Nippon Shokuhin Kako Co., Ltd.

<(C) component>
Polyvinyl alcohol, “Product name: Gohsenol EG-05PW”, manufactured by Nippon Synthetic Chemical Industry Co., Ltd.
・ Methylcellulose, “Product name: Metroles SM-4000”, manufactured by Shin-Etsu Chemical Co., Ltd.

<(C ′) component, (C) component comparison component>
Hydroxypropyl cellulose, “Product name: HPC-SSL”, manufactured by Nippon Soda Co., Ltd.
・ Hydroxypropyl methylcellulose, “Product name: Metroles 60SH-4000”, manufactured by Shin-Etsu Chemical Co., Ltd. Weight average molecular weight 300,000 (g / mol).
Polyvinylpyrrolidone, “Product name: Kollidon 90F”, manufactured by BASF Japan. Weight average molecular weight 1 million (g / mol).

<(D) component>
-L-menthol, manufactured by Nagaoka Jitsugyo Co., Ltd.
・ Dl-Camphor, manufactured by Ogi Pharmaceutical Co., Ltd.

<Optional component>
・ Erythritol, “Product name: Erythritol 100M”, manufactured by Bussan Food Science Co., Ltd.
・ Corn starch, “Product name: Pharmacopoeia Matsutani Cornstarch”, manufactured by Matsutani Chemical Industry Co., Ltd.
Hydroxypropyl cellulose, “Product name: HPC-SSL”, manufactured by Nippon Soda Co., Ltd.
・ Lactose hydrate, “Product name: Dilactose”, manufactured by Freund Corporation.
-Crystalline cellulose, "Product name: UF-702", manufactured by Asahi Kasei Chemicals Corporation.
・ Crospovidone, “Product name: Kollidon CL-SF”, manufactured by BASF Corporation.
・ Dl-Camphor, manufactured by Ogi Pharmaceutical Co., Ltd.
-Magnesium stearate, manufactured by Taihei Chemical Industry Co., Ltd.
・ Reduced maltose starch syrup, “Product name: Amarty Syrup”, manufactured by Mitsubishi Corporation Foodtech Co., Ltd.
-D-sorbitol solution, “Product name: Sorbit D-70”, manufactured by Mitsubishi Corporation Food Tech Co., Ltd.
・ Sucrose, “Product name: Kamishi white sugar”, manufactured by Mitsui Sugar Co., Ltd.
Gelatin, “Product name: Nippi Gelatin AP-270”, manufactured by Nippi Corporation.
-Gelling agent preparation (carrageenan 22.0% by weight, locust bean gum 19.0% by weight, potassium chloride 7.5% by weight, calcium lactate 7.0% by weight, dextrin 44.5% by weight), “Product Name: NEWGELIN LB-98F ", manufactured by Mitsubishi Corporation Food Tech Co., Ltd.
・ Citric acid, manufactured by Fuso Chemical Industry Co., Ltd.
・ Sodium citrate, manufactured by Fuso Chemical Industry Co., Ltd.

(Granulated material (granular agent))
<Examples 1 to 10, Comparative Examples 1 to 6>
In accordance with the composition of Tables 1 and 2, the (A) component and the (C) component are added to and mixed in a mixing granulator (high speed mixer, manufactured by Earth Technica Co., Ltd.) and heated to 80 ° C. or higher (A ) The ingredients were melted. Then, (B) component was thrown into the said mixing granulator, and it stirred, and obtained the mixture of (A) component, (B) component, and (C) component. In a state where the mixture was cooled to room temperature (25 ° C.) and kept warm, the mixture was granulated with stirring under the conditions of an agitator rotation speed of 200 rpm and a chopper rotation speed of 2000 rpm to obtain a granulated product. The granulated product was sieved through a vibration sieve (manufactured by Dalton Co., Ltd.) to obtain the granulated product of Examples 1 to 10 (average particle size 150 μm).
Granules of Comparative Examples 1 to 3 were obtained in the same manner as in Example 1 except that the component (B) and / or the component (C) were not used. Moreover, the granulated material of Comparative Examples 4-6 was obtained like Example 1 except having replaced with (C) component and having used (C ') component.
In addition, the granulated material of Examples 1-10 and Comparative Examples 1-6 is manufactured by the melt granulation method.

<Examples 11-15, Comparative Examples 7-8>
According to the composition of Table 3, agitator rotation speed while adding water to the mixture obtained by adding (A) component, (B) component, (C) component and lactose hydrate to the mixing granulator A kneaded product was obtained by kneading under conditions of 300 rpm and chopper rotation speed 2000 rpm. The amount of water added was 10 to 20% by mass with respect to the total mass of the mixture. The obtained kneaded product was extruded and granulated using a wet extrusion granulator (“Dome Gran” manufactured by Fuji Paudal Co., Ltd.) to obtain a granulated product. This granulated product is shelf-dried (50 ° C, 2-3 hours) using a dryer (fan constant temperature and temperature chamber, manufactured by Yamato Kagaku Co., Ltd.) and then rectified by applying a rectifier (Quadrocomil, manufactured by Paulec Co., Ltd.) Granules of Examples 11 to 15 were obtained. The average particle diameter of the granulated materials of Examples 11 to 15 was 1000 to 1500 μm, and the water content was 0.5 to 3.0 mass%.
A granulated product of Comparative Example 7 was obtained in the same manner as Example 11 except that the component (B) was not used. Further, a granulated product of Comparative Example 8 was obtained in the same manner as Example 11 except that the component (C ′) was used instead of the component (C).
In addition, the granulated material of Examples 11-15 and Comparative Examples 7-8 is manufactured by the extrusion granulation method.

(Orally disintegrating tablets)
<Examples 16 to 31, Comparative Examples 9 to 11>
According to the composition of Table 4, the granulated product of each of the above examples, granules obtained by mixing erythritol and corn starch and granulated with a binding solution in which hydroxymethylcellulose is dissolved in water, crystalline cellulose, crospovidone, Then, magnesium stearate was charged into a mixer (Bole container mixer, manufactured by Kotobuki Giken Kogyo Co., Ltd.) and mixed for 20 minutes to obtain a tableting mixture. This tableting mixture was tableted using a tableting machine (LIBRA, manufactured by Kikusui Seisakusho Co., Ltd.) to produce tablets of Examples 16 to 25 and Comparative Examples 9 to 11. The tablets in each example were Sumi square flat tablets with a tablet diameter of 9.0 mm. Moreover, the tableting pressure was adjusted so that the tensile strength of the tablet of each example might be 90-120 N / cm < ² >.
Further, according to the composition of Table 5, except that the granulated product of Example 3, the component (D), the granule, crystalline cellulose, crospovidone, and magnesium stearate were charged into the mixer. The tablets of Examples 26 to 31 were produced in the same manner as Example 16.

(Gummy agent)
<Example 32, Comparative Examples 12-13>
After swelled with gelatin, the solution was heated to 60 ° C. to prepare a solution in which gelatin was dissolved. Reduced maltose starch syrup, D-sorbitol and sucrose were added to this solution, and water was added while stirring, and the temperature was raised to 130 ° C. Thereafter, the solution was cooled, and when the temperature reached 60 ° C., the granulated product of Example 3 was added and stirred, then dispensed into a hemispherical mold (about 1.5 g), cooled at room temperature, and dried. Thus, the gummi preparation of Example 32 was produced. The composition of each component described above was in accordance with Table 6.
Moreover, it replaced with the granulated material of Example 3, and the gummi agent of Comparative Examples 12-13 was carried out similarly to Example 32 except having used the granulated material of Comparative Example 2 or the granulated material of Comparative Example 3. Manufactured.

(Jelly agent)
<Example 33, Comparative Examples 14-15>
According to the composition of Table 7, a gelling agent formulation (a mixture of carrageenan, locust bean gum, potassium chloride, calcium lactate and dextrin) and sucrose were added to purified water and stirred to prepare a solution. To this solution, citric acid and sodium citrate were added and heated to 100 ° C. to dissolve the above components. Thereafter, the solution was cooled, and when the temperature reached 60 ° C., the granulated product of Example 3 was added and stirred, and then dispensed into a stick-shaped three-sided sealed container (10 mL, about 9 g). The jelly agent of Example 33 was produced by cooling with The composition of each component described above was in accordance with Table 7.
Instead of the granulated product of Example 3, the jelly agents of Comparative Examples 14 to 15 were produced in the same manner as in Example 33 except that the granulated product of Comparative Example 2 or the granulated product of Comparative Example 3 was used. did.

Tables 1 to 3 show the compositions (blending components, content (parts by mass)) of the obtained granulated product of each example. In Tables 1-3, “I” of the granulation method indicates that the granulated product was produced by the melt granulation method, and “II” indicates that the granulated product was produced by the extrusion granulation method. Show.
In Tables 4-7, the composition (formulation component, content (mg)) of the obtained oral preparation of each example is shown.
In Tables 1-7, when there is no description of a compounding quantity, the component is not mix | blended.
In Tables 1-7, content of a compounding component shows a pure conversion amount.

Moreover, about the granulated material of each example, the elution rate of ibuprofen, the irritation | stimulation suppression property derived from ibuprofen, food texture, and caking suppression property were evaluated as follows. About the oral formulation of each case, the elution rate of ibuprofen, irritation suppression derived from ibuprofen, and food texture were evaluated as follows.
Each evaluation result is shown in Tables 1-7.

<Evaluation of dissolution rate>
The dissolution rate of the granulated product or oral preparation (containing 65 mg of ibuprofen) according to the dissolution test method (paddle method, 50 rpm, dissolution test first solution (pH 1.2)) listed in the Japanese Pharmacopoeia (16th revision) Asked. Using the first dissolution test solution (pH = 1.2), the dissolution rate (%) of ibuprofen at 5 minutes was calculated. The calculated dissolution rate was evaluated according to the following evaluation criteria, and 3 or more was determined to be acceptable. If the dissolution rate at 5 minutes is 20% or more, the headache improvement rate at 60 minutes after taking is good.
≪Evaluation criteria for dissolution rate≫
5: 30% or more.
4: 25% or more and less than 30%.
3: 20% or more and less than 25%.
2: 10% or more and less than 20%.
1: Less than 10%.

<Evaluation criteria for caking suppression>
A container without a lid is filled with 300 g of the granulated product of each example and left to stand at 25 ° C. and a relative humidity of 60% for 10 days. Thereafter, the granulated product is observed visually and by touch, and granulated. The caking suppression property in the moisture absorption state of the object was evaluated according to the following evaluation criteria, and 3 or more was determined to be acceptable. If the evaluation is 3 or more, for example, when an oral preparation is prepared by mixing the granulated product and optional components, the consolidated granulated product can be broken down, and the content of the drug is uniform. It is easy to adjust the oral formulation.
≪Evaluation criteria for caking suppression≫
5: The granulated product is in a free-flowing state and no caking is observed.
4: The granulated material is very weakly consolidated, and breaks down as soon as it is lightly pressed with a finger.
3: The granulated material is weakly consolidated, and collapses when pressed lightly with a finger.
2: The granulated product is strongly consolidated, and collapses when pressed strongly with a finger.
1: The granulated material is very strongly consolidated and does not collapse even when pressed strongly with a finger.

<Evaluation of stimulus suppression>
Five panelists scored the irritation felt when taking the granulated product of each example or the oral preparation of each example (containing 65 mg of ibuprofen) without water according to the following criteria for determining the inhibition of irritation. Then, the total score was calculated and evaluated according to the following evaluation criteria for stimulus suppression, and 3 or more was determined to be acceptable.
<< Judgment criteria for stimulus suppression >>
5 points: I do not feel irritation.
4 points: A slight stimulus is felt.
3 points: Slight irritation.
2 points: I feel irritation.
1 point: I feel a strong stimulus.
≪Evaluation criteria for stimulation inhibition≫
5: Total score is 22 to 25 points.
4: Total score is 18 to 21 points.
3: The total score is 14 to 17 points.
2: Total score is 10 to 13 points.
1: Total score is 9 or less.

<Evaluation of texture>
The five panelists took each granule or oral preparation (containing 65 mg of ibuprofen) without water and applied the sheer to the tongue and upper jaw to dissolve it. The score was assigned according to the criteria. And the total score was calculated, it evaluated according to the evaluation criteria of the following food texture, and 3 or more was set as the pass. In addition, if it is 2 points or less according to the following criteria, it feels rough when taken, and the takeability is poor, and when taking an oral preparation, The granulated material must be dissolved, which can cause a strong irritation.
≪Criteria for eating texture≫
5 points: Does not feel rough.
4 points: I feel a little rough.
3 points: I feel a little rough.
2 points: Feels rough.
1 point: I feel quite rough.
<< Evaluation criteria for texture >>
6: 23-25 points.
5: 20-22 points.
4: 17-19 points.
3: 14-16 points.
2: 11-13 points.
1: 10 points or less.

As shown in Tables 1 to 3, the granulated products of Examples 1 to 15 to which the present invention was applied were excellent in ibuprofen dissolution and irritation suppression. Furthermore, the food texture was good and the caking inhibitory property was also excellent.
Moreover, as shown to Tables 4-7, the oral formulation of Examples 16-33 to which this invention was applied was excellent in the elution property and irritation | stimulation suppression property of ibuprofen. Furthermore, the texture was excellent.
On the other hand, it is manufactured by the melt granulation method, (B) component, granulated product not containing one or both of (C) component (Comparative Examples 1 to 3), (P) polyvinyl pyrrolidone instead of component The granulated product to be contained (Comparative Example 6) was insufficient in ibuprofen dissolution and irritation suppression. In the granulated product (Comparative Examples 4 and 5) containing hydroxypropylcellulose or hydroxypropylmethylcellulose instead of the component (C), the elution property of ibuprofen was not sufficient. Moreover, the favorable granulation thing of Comparative Examples 1-6 was not obtained. Further, the granulated products of Comparative Examples 1 and 3 did not have a good texture.
The granulated product (Comparative Example 7) which is manufactured by the extrusion granulation method and does not contain the component (B), and the granulated product (Comparative Example 8) which contains hydroxypropyl cellulose instead of the component (C) are eluted with ibuprofen. Sex and irritation suppression were not sufficient. In addition, the granulated products of Comparative Examples 7 and 8 did not have good consolidation inhibitory properties. Furthermore, the granulated product of Comparative Example 7 did not have a good texture.
Oral preparations (Comparative Examples 9 to 15) containing any granulated product of Comparative Examples 1 to 3 did not have sufficient ibuprofen dissolution and irritation suppression properties. Furthermore, the oral preparations of Comparative Examples 9 and 11 did not obtain a good texture.
From the above results, it was confirmed that by applying the present invention, a granulated product and an oral preparation excellent in the dissolution property and irritation suppression property of ibuprofen were obtained.

Claims (9)

  A granulated product containing ibuprofen (A), β-cyclodextrin (B), and at least one selected from the group consisting of polyvinyl alcohol and methylcellulose (C).   The granulated product according to claim 1, wherein a mass ratio represented by the component (B) / the component (A) is 0.4 or more.   The granulated product according to claim 1 or 2, wherein a mass ratio represented by the component (C) / the component (A) is 0.03 or more.   The oral formulation containing the granulated material as described in any one of Claims 1-3.   The oral preparation according to claim 4, wherein the dosage form is a granule, tablet, pill, gummi or jelly.   Furthermore, it contains at least one (D) selected from the group consisting of l-menthol, dl-menthol, d-camphor and dl-camphor, and the mass ratio represented by the component (D) / the component (A) is The oral preparation according to claim 5, which is 0.003 or more.   The oral preparation according to claim 5 or 6, wherein the dosage form is a tablet, and the tablet is a chewable tablet or an orally disintegrating tablet. It is a manufacturing method of the granulated material according to any one of claims 1 to 3,
The manufacturing method of the granulated material which granulates the raw material containing the said (A) component, the said (B) component, and the said (C) component by a melt granulation method or a wet granulation method, and obtains a granulated material.   The manufacturing method of an oral formulation provided with the process of obtaining a granulated material with the manufacturing method of the granulated material of Claim 8, and the process of mix | blending the granulated material obtained at the said process.

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