JP5870775B2 - Tablet and production method thereof - Google Patents

Description

  The present invention relates to a tablet excellent in dissolution and disintegration and a method for producing the tablet.

  Propionic acid non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and pyranoacetic acid non-steroidal anti-inflammatory drugs such as etodolac have excellent anti-inflammatory, analgesic and antipyretic effects and have relatively few side effects, thus analgesic / antipyretic drugs And widely used as a component of cold medicine. In order for tablets containing these drugs to exert their pharmacological effects quickly, the tablets must disintegrate rapidly in the stomach, and then the active ingredients must be rapidly dissolved (dissolved). However, poorly water-soluble propionic acid-based non-steroidal anti-inflammatory agents and pyranoacetic acid-based non-steroidal anti-inflammatory agents have a problem in that rapid disintegration and elution (dissolution) do not proceed and it is difficult to exert rapid effects.

JP-A 56-110612 Special table 2003-516341 gazette

  Various techniques have been studied for the purpose of solving the problems related to disintegration and dissolution of poorly soluble drugs. For example, Japanese Patent Application Laid-Open No. 56-110612 discloses a compression-molded product obtained by blending a poorly soluble drug with polyvinylpyrrolidone, hydroxypropylcellulose or the like (or further with a surfactant), and granulating by a fluidized bed granulation method. It is disclosed that it has shown excellent disintegration and dissolution properties compared to compression molded products using spray drying and other wet granulation methods. However, although the detailed mechanism is unknown, in our study, fluid-bed granulation and other wet processes using a general-purpose binder solution such as hydroxypropylcellulose only for poorly water-soluble nonsteroidal anti-inflammatory agents. When granulation was performed, the dissolution property of the granulated particles was improved, but it was found that the disintegration property of the tablet, which is the previous stage, was significantly lowered and the rapid effect could not be exhibited.

  Japanese Patent Application Publication No. 2003-516341 discloses a method for improving the dissolution property by melting ibuprofen, blending a disintegrant and a surfactant, and solidifying. However, it was also found that the disintegration is significantly delayed when using a granule to which a surfactant is added in a melted state of ibuprofen.

  As described above, it has been difficult to prepare a tablet containing a poorly water-soluble non-steroidal anti-inflammatory agent that satisfies the disintegration property and dissolution property by the conventional technique. This invention is made | formed in view of the said situation, and it aims at providing the tablet containing the poorly water-soluble nonsteroidal anti-inflammatory agent which satisfies disintegration property and dissolution property.

  As a result of intensive studies to achieve the above object, the present inventors have found that (A) a poorly water-soluble nonsteroidal anti-inflammatory agent, (B) a sucrose fatty acid ester having a freezing point of 30 ° C. or higher and an HLB of 9 or higher, and (C A) a compound selected from light anhydrous silicic acid, hydrous silicon dioxide and sodium stearyl fumarate; (D) a compound selected from crystalline cellulose, silicified crystalline cellulose and powdered cellulose; and (E) a disintegrant. B) / (A) The mass ratio of the component (A) and the component (B) represented by (A) is 0.03 to 0.4, and it is found that both disintegration and dissolution can be achieved. The present invention has been achieved.

Accordingly, the present invention provides the following tablets and tablet production methods.
[1]. (A) one or more selected from ibuprofen, ketoprofen and naproxen ;
(B) a sucrose fatty acid ester having a freezing point of 30 ° C. or higher and an HLB of 13 or higher;
(C) a compound selected from light anhydrous silicic acid, hydrous silicon dioxide and sodium stearyl fumarate;
(D) a compound selected from crystalline cellulose, silicified crystalline cellulose and powdered cellulose;
(E) a disintegrating agent, the average particle size of the component (A) is 50 μm or less, and the mass ratio of the component (A) and the component (B) represented by (B) / (A) is , 0.0 4-0. 27 der is, the content weight ratio of the (C) / represented by (A) (A) component (C) is 0.005 to 0.1, with (D) / (A) The mass ratio of the component (A) and the component (D) represented is 0.22 to 5.0, and the components (A) and (E) represented by (E) / (A) The content mass ratio of the tablet is 0.03-0.17.
[2]. Component (B), sucrose stearate, sucrose fatty acid ester selected from sucrose palmitate and sucrose myristate [1] Symbol placing tablets.
[3]. (A) an average particle diameter of the component, characterized in that at 25μm or less [1] or [2] Symbol placing tablets.
[4]. The component (E) is a disintegrant selected from low substituted hydroxypropylcellulose, carmellose, croscarmellose sodium, crospovidone, sodium carboxymethyl starch and carmellose calcium, according to any one of [1] to [ 3 ]. Tablets.
[5]. The components (A) and (B) are dry-mixed in advance, the components (C) to (E) are blended and mixed in the obtained dry mixture, and the mixture is tableted [1. ] The manufacturing method of the tablet in any one of [ 4 ].
[6]. (A) component and (B) component are dry-mixed beforehand, (C)-(E) component is mix | blended with the obtained dry-type mixture, and after dry-granulating, this dry-granulated material is tableted. The manufacturing method of the tablet in any one of [1]-[ 4 ] characterized by the above-mentioned.
[7]. After the (A) component and the (B) component are previously melt granulated, wet granulated or co-ground, and then the components (C) to (E) are blended into the resulting product, followed by dry granulation The method for producing a tablet according to any one of [1] to [ 4 ], wherein the dry granulated product is tableted.

  ADVANTAGE OF THE INVENTION According to this invention, the tablet containing the propionic acid type non-steroidal anti-inflammatory agent which satisfies disintegration and dissolution property can be provided.

Hereinafter, the present invention will be described in detail.
The tablet of the present invention comprises (A) a poorly water-soluble non-steroidal anti-inflammatory agent, (B) a sucrose fatty acid ester having a freezing point of 30 ° C. or higher and an HLB of 9 or higher, (C) light anhydrous silicic acid, hydrous silicon dioxide and fumar It contains a compound selected from sodium stearyl acid, (D) a compound selected from crystalline cellulose, silicified crystalline cellulose and powdered cellulose, and (E) a disintegrant, and is represented by (B) / (A) ( It is a tablet whose content mass ratio of A) component and (B) component is 0.03-0.4.

(A) A poorly water-soluble non-steroidal anti-inflammatory agent As a poorly water-soluble non-steroidal anti-inflammatory agent, propionic acid-based nonsteroidal anti-inflammatory agents such as ibuprofen, loxoprofen, naproxen, ketoprofen and piroxicam, and pyranoacetic acid-based nonsteroidal anti-inflammatory agents such as etodolac An agent etc. are mentioned, It can use individually by 1 type or in combination of 2 or more types. These components have excellent anti-inflammatory, analgesic and antipyretic effects. Among these, ibuprofen, ketoprofen, naproxen, and etodolac are preferable, and ibuprofen is more preferable. Since this invention can improve the elution property of a poorly water-soluble drug, even if it is a drug having a solubility in water at 20 ° C. of 0 to 30 mg / mL and 0 to 10 mg / mL, high elution is obtained. Can do.

  The average particle diameter of the component (A) is not particularly limited, but is preferably as the particle diameter is small, preferably 75 μm or less, more preferably 50 μm or less, further preferably 30 μm or less, and 25 μm or less, 20 μm or less, or 15 μm or less. Particularly preferred in order. Dissolution is improved by reducing the particle size. (A) The particle diameter of a component can be adjusted with common manufacturing apparatuses, such as a pin mill and a jet mill, for example. The pulverization may be the component (A) alone or co-pulverized with other components. In addition, the measuring method of an average particle diameter is measured with a laser diffraction type particle size distribution measuring apparatus (SALD-2200 manufactured by Shimadzu Corporation), and the ratio is calculated by number%.

  The component (A) may be a co-pulverized product, and the excipient used for co-pulverization is not particularly limited, but a cellulose excipient is preferred, and as the cellulose excipient, crystalline cellulose, carboxymethyl cellulose, low-substituted hydroxypropyl cellulose , Silicified crystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose and the like. (D) component mentioned later may be mix | blended a part at the time of co-grinding with (A) component, when co-grinding (A). The component (D) that can be used for co-grinding with the component (A) is preferably 50% by mass or less of the entire component (D).

  (A) Content of a component can be arbitrarily set in the range which does not have a problem in manufacturability, but 10-90 mass% in 1 tablet is preferable from a viewpoint of manufacturability and disintegration, and 10-60 mass% is more. Preferably, 10 to 45% by mass is more preferable. If the content of the component (A) in one tablet is less than 10% by mass, the tablet disintegration is excellent, but the tablet may become large and difficult to take. Moreover, when the ratio of (A) component in 1 tablet is too high, depending on the kind of (A) component, tableting troubles, such as adhesion, may arise.

(B) Sucrose fatty acid ester having a freezing point of 30 ° C. or higher and an HLB of 9 or more The sucrose fatty acid ester having a freezing point of 30 ° C. or higher is not particularly limited. Can be used alone or in combination of two or more. By using a sucrose fatty acid ester having a freezing point of 30 ° C. or higher, it is easy to handle in production and the elution is improved. Of these, sucrose stearate is preferable. In addition, HLB of 9 or more is used. Furthermore, the thing of 11 or more is preferable, the thing exceeding 11 is more preferable, and the thing of 13 or more is further more preferable. In addition, although HLB changes with the ratio of a monoester, etc., those with high HLB improve disintegration property and elution property. In addition, the measuring method of HLB is a Griffin method, and when it is 2 or more types, it is the average value.

  Although content of (B) component is not specifically limited, 0.01-30 mass% in 1 tablet is preferable, and 0.1-25 mass% is more preferable. Moreover, since the fluidity | liquidity at the time of mixing and granulation will become more favorable when an upper limit shall be 20 mass% or less, from the said viewpoint, 15 mass% or less is more preferable, and 10 mass% or less is especially preferable.

  The content mass ratio of the component (A) and the component (B) represented by (B) / (A) is 0.03 to 0.4 from the point of achieving both excellent disintegration and dissolution. 0.03-0.33 is preferable, 0.04-0.3 is more preferable, 0.05-0.25 is further more preferable, and 0.07-0.25 is especially preferable. When (B) / (A) is less than 0.03, the dissolution property becomes insufficient, and when it exceeds 0.4, the disintegration property decreases, and the dissolution property of the tablet decreases accordingly. In addition, although total content of (A) component and (B) component is not specifically limited, 10-70 mass% in 1 tablet is preferable, and 35-50 mass% is more preferable.

  The present invention improves the elution of the component (A) by first using the component (A) and the component (B) together. Surprisingly, however, it was found that when tablets were formed by tableting, tablet disintegration was delayed as compared with the case of component (A) alone, and as a result, dissolution of component (A) in tablets was worse. . Although this mechanism is unknown, it is considered that the tablet was formed with the binding force derived from the component (A) by tableting. In addition to the above-mentioned problems, the present invention further uses the following components (C) and (D) to prevent disintegration delay in tablets, and to obtain tablets with excellent solubility and disintegration. It is. The mechanism by which (C) and (D) components improve disintegration is unclear, but (C) the hydrophilic lubricant coats the surface of (A) component, so By suppressing the formation of interparticle bonding force, and (D) a high moldability excipient is blended, the bonding force derived from component (D) is given priority over the bonding force derived from component (A). It is expected to be demonstrated.

(C) Compound selected from light anhydrous silicic acid, hydrous silicon dioxide and sodium stearyl fumarate (C) The component is a hydrophilic lubricant. By using such a hydrophilic lubricant, the surface wettability of the component (A) is improved and the dissolution property is improved. In addition, by using the component (C), the decay delay can be suppressed. Although this mechanism is not clear, it is considered that these (C) components adhere to the surface of the (A) component to suppress the formation of interparticle bonding force between the (A) components. Furthermore, tableting troubles such as adhesion and binding due to the physical properties of the component (A) can be suppressed by using these hydrophilic lubricants. (C) A component can be used individually by 1 type or in combination of 2 or more types, Especially, a light silicic acid anhydride is preferable.

  Although content of (C) component is not specifically limited, 0.01-20 mass% in 1 tablet is preferable from the point of tablet disintegration property and the ease of handling of powder, and 0.02-10 mass% is preferable. More preferably, 0.03-5 mass% is further more preferable.

  The blending ratio of the component (C) is not particularly limited, but the content mass ratio of the component (A) and the component (C) represented by (C) / (A) is preferably 0.001 to 0.1. 0.005-0.07 is more preferable, 0.007-0.05 is further more preferable, and 0.01-0.05 is particularly preferable. By making (C) / (A) 0.001 or more, the disintegration is good, and by making it less than 0.1, the fine powder amount is within an appropriate amount range and the handling property is good.

(D) Compound selected from crystalline cellulose, silicified crystalline cellulose and powdered cellulose (D) The component is a highly moldable excipient. By using such a highly moldable excipient, the disintegration is unexpectedly improved. Although this mechanism is not clear, it is considered that the tablet is prevented from being formed by the interparticle binding force derived from the component (A), and the disintegration is improved. (D) A component can be used individually by 1 type or in combination of 2 or more types, Especially, crystalline cellulose and silicified crystalline cellulose are preferable.

  Although content of (D) component is not specifically limited, 0.5-95 mass% in 1 tablet is preferable from the point of manufacturability, 5-75 mass% is more preferable, 10-50 mass% is further more preferable. .

  The blending ratio of the component (D) is not particularly limited, but the content mass ratio of the component (A) and the component (D) represented by (D) / (A) is preferably 0.02 or more. The above is more preferable, and 0.5 or more is more preferable. If the blending ratio of the components (A), (B), (C) and (E) is within an appropriate range, even if the ratio of the component (D) becomes too high, there is an adverse effect on disintegration and elution properties. However, from the viewpoint of tablet dosing, (D) / (A) is preferably 5.0 or less.

(E) Disintegrating agent Not only improves the disintegration property of the tablet by blending the component (E), but also disintegrates the disintegrated tablet pieces finely in water and improves the dissolution property. Examples of the disintegrant include low-substituted hydroxypropylcellulose, carmellose, croscarmellose sodium, crospovidone, carboxymethyl starch sodium, carmellose calcium, and the like, and these may be used alone or in combination of two or more. it can. Among these, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and carboxymethyl cellulose are preferable, and low-substituted hydroxypropyl cellulose and carboxymethyl cellulose are more preferable.

  Although content of (E) component is not specifically limited, 0.01-50 mass% in 1 tablet is preferable from the point of manufacturability and administration property, 0.1-30 mass% is more preferable, 0.5 -20 mass% is further more preferable.

  (E) Although the compounding ratio of a component is not specifically limited, 0.01-0.3 are preferable for the mass ratio of (A) component and (E) component represented by (E) / (A), 0.03-0.2 is more preferable, and 0.05-0.1 is more preferable. When (E) / (A) exceeds 0.3, the disintegration may be significantly delayed depending on the type of disintegrant.

  In addition to the above components (A) to (E), the tablet of the present invention includes other physiologically active ingredients and additives as long as the effects of the present invention are not impaired and the physical properties and storage stability of the tablet are not impaired. May be blended. These can be used alone or in appropriate combination of two or more.

Examples of the physiologically active component include antipyretic analgesic components other than the component (A) (for example, piroxicam, meloxicam, ampiroxicam, serocoxib, rofecoxib, thiaramide, acetaminophen, etenzamide, sulpyrine, etc.), sedative hypnotic components (for example, allyl Isopropylacetylurea, bromvalerylurea, etc.), antihistamine components (for example, isothipenzil hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, dipheterol hydrochloride, triprolidine hydrochloride, tripelenamine hydrochloride, tonsylamine hydrochloride, phenetazine hydrochloride, methodirazine hydrochloride, diphenhydramine salicylate, diphenyldisulfonic acid Carbinoxamine, alimemazine tartrate, diphenhydramine tannate, diphenylpyraline teocrate, mebhydro napadisylate , Promethazine methylene disalicylate, carbinoxamine maleate, dl-chlorpheniramine maleate, chlorpheniramine maleate, dipheterol phosphate, etc.), central excitatory components (eg sodium benzoate caffeine, caffeine, anhydrous Caffeine etc.), antitussive expectorant ingredients (codeine phosphate, dextromethorphan hydrobromide, dimemorphan phosphate, tipepidine hibenzate, methoxyphenamine hydrochloride, trimethquinol hydrochloride, carbocysteine, acetyl Cysteine, ethylcysteine, dl-methylephedrine, bromhexine hydrochloride, serrapeptase, lysozyme chloride, ambroxol, theophylline, aminophylline), antacid (dried aluminum hydroxide gel, aluminum glycinate), Vita Emission components (e.g., vitamins B ₁ and its derivatives and salts thereof, vitamin B ₂ and its derivatives and salts thereof, vitamin C and its derivatives and their salts, hesperidin and its derivatives, and the like salts thereof) such as mentioned It is done.

  Examples of additives include binders, excipients other than the component (D), fragrances, pigments, sweeteners, acidulants and the like. Specifically, starch, pregelatinized starch, sucrose, gelatin, gum arabic powder, polyvinylpyrrolidone, pullulan, dextrin and the like can be used as the binder. As the excipient, lactose, corn starch, powdered sugar, mannitol, L-cysteine and the like can be used. Examples of the fragrances include menthol, limonene, plant essential oil (mint oil, mint oil, lychee oil, orange oil, lemon oil, etc.) and the like. Examples of the sweetener include saccharin sodium, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, sucralose and the like. As the acidulant, citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, or a salt thereof can be used. These physiologically active ingredients and additives can be blended both in the dry granulated granule and outside the dry granulated granule in the tablet. Among these physiologically active ingredients and additives, metal salts such as aluminum salts, magnesium salts and silicates are preferably blended outside the dry granules. As these metal salts, metal salts containing aluminum are preferable, and dry aluminum hydroxide gel, aluminum glycinate, magnesium aluminate metasilicate, and synthetic hydrotalcite are preferable, and dry aluminum hydroxide gel is particularly preferable. By blending these inorganic salts, disintegration of the tablet is further improved, and problems such as adhesion during tableting are suppressed.

Examples of the method for producing the tablet of the present invention include the following methods.
(I) A method in which the components (A) to (E) are dry-mixed and the dry mixture is tableted.
(II) A method in which the components (A) and (B) are dry-mixed in advance, the components (C) to (E) are blended and mixed in the obtained dry mixture, and the mixture is tableted.
(III) (A) component and (B) component are dry-mixed beforehand, (C)-(E) component is mix | blended with the obtained dry-type mixture, and after dry-granulating, this dry-granulated material is made into How to tablet.
(IV) The components (A) and (B) are preliminarily melt granulated, wet granulated, or co-ground, and then the components (C) to (E) are blended into the resulting product, followed by dry granulation. A method of tableting this dry granulated product after granulation. In the case of simple mixing, dry mixing, dry granulation, melt granulation, wet granulation, co-grinding, etc. are included, and “mixing” of the components (C) to (E) in the above (II) is “ “Dry mixing” is preferred.

  In the present invention, “dry mixing” means mixing a mixture without adding a liquid such as water. “Dry granulation” is a method of granulating without using a liquid such as water, and includes compression granulation. “Melt granulation” is a method in which a drug is melted into a liquid state by a method such as heating, and then cooled and solidified for granulation. “Wet granulation” is a method of granulating by adding a liquid such as water, and includes fluidized bed granulation, stirring granulation, rolling granulation and the like. “Co-grinding” means that two or more kinds of materials to be crushed (for example, a drug and an excipient, two or more different drugs, or two or more different excipients) are pulverized together by a pulverizer such as a pin mill. Is the method.

  Components (A) to (E) may be dry-mixed, and the resulting dry-type mixture may be compressed by direct compression, but before tableting, (A) component and (B) component are dry-mixed in advance. And it is preferable to mix | blend (C)-(E) component with this mixture. This further improves the dissolution property. Although this mechanism is not clear, it is expected that the component (B) is coated on the surface of the component (A), the wettability of the component (A) is improved, and the elution is further improved. Moreover, when (A) component and (B) component are dry-mixed previously, (C) component can also be mix | blended simultaneously. (C) By mix | blending a component together, the surface adhesive force of (A) component is reduced and disintegration improves further. When (A) component and (B) component are dry-mixed beforehand, (C)-(E) component is mix | blended with this mixture, (A) component, (B) component, and (C) component previously And (D) and (E) components may be blended and mixed and directly subjected to the tableting process, or may be subjected to the tableting process after dry granulation. Examples of dry granulation include compression granulation using a roller compactor.

  Moreover, although (A) component and (B) component may be melt-granulated, wet-granulated, or co-ground previously, in that case, (C)-(E) component is mix | blended and mixed, Rather than tableting this mixture, the dry granulated product may be tableted after blending the components (C) to (E) and dry granulating. Disintegration and dissolution properties are further improved by blending the components (C) to (E) and dry granulating before tableting. In this case, part or all of the component (C) may be added simultaneously during co-grinding. When dry granulation is performed before tableting, the components (A) and (B) can be selected from dry mixing, melt granulation, wet granulation or co-grinding, but dry mixing, melt granulation and co-grinding are preferred. Dry mixing and co-grinding are more preferable. Prior to dry granulation, when the components (A) and (B) are dry-mixed or co-ground, the surface adhesion of the component (A) is less likely to increase than when wet granulation or melt granulation is performed. Thereby, disintegration of the tablet is difficult to delay.

  In addition, the average particle diameter of the dry granulated product can be arbitrarily set as long as there is no problem in manufacturability. The range of the average particle diameter of the dry granulated product is preferably 50 to 850 μm, more preferably 75 to 700 μm, and further preferably 100 to 550 μm. If the particle size of the dry granulated product is less than 50 μm, depending on the type of component (A), problems such as poor filling and adhesion may occur during tableting.

  The mixing method is not particularly limited, and can be performed using a known mixer such as a Boule mixer, a double cone mixer, a V-type mixer, or a container blender. Dry granulation can also be produced by a known method. For example, it can be produced by a compression granulator such as a roller compactor. The flakes obtained by roller compression can be pulverized using a known pulverizer such as a fiore or roll granulator.

  The tablet of the present invention may be a single layer tablet composed of a single layer, or may be a multilayer tablet in which a plurality of layers are laminated. In the case of a single-layer tablet, it can be prepared by tableting the mixture. For tableting, a rotary tableting machine such as a known tableting machine such as LIBRA (product name, manufactured by Kikusui Seisakusho Co., Ltd.), HP-AP-MS type (product name, manufactured by Hata Plant) A lock molding machine or the like can be used. In the case of a multilayer tablet, any one of the mixture containing the components (A) to (E) and other additives can be blended in the first layer, and the other can be blended in the second layer. After laminating the second layer, compression molding is preferably performed between the upper and lower eyelids.

  The obtained tablets may be coated with a coating agent as necessary. As such a coating agent, it is preferable to select one that does not significantly impair the disintegration property of the present invention, and among them, a water-soluble polymer compound and a plasticizer are preferable. Specifically, celluloses such as carmellose, hydroxypropylcellulose, hydroxypropylmethylcellulose, low-substituted hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose, ethylcellulose; gum arabic, carboxyvinyl polymer, povidone, crospovidone, polyvinyl alcohol, polyacryl Acid, monosaccharide, polysaccharide more than disaccharide (sugar (granulated sugar etc.), lactose, maltose, xylose, isomerized lactose etc.), sugar alcohol (palatinite, sorbitol, lactitol, erythritol, xylitol, reduced starch saccharified product, multi Tall, mannitol, etc.), starch syrup, isomerized sugar, oligosaccharide, sucrose, trehalose, reduced starch saccharified product (reduced starch degradation product) and the like. Examples of the plasticizer include those described in official documents such as Japanese Pharmacopoeia (Hirokawa Shoten) such as triethyl citrate and triacetin, and pharmaceutical additive standards (Pharmaceutical Daily Inc.). These can be used individually by 1 type or in combination of 2 or more types. The amount of the coating agent used is preferably about 0.5 to 1.5% by mass relative to the whole tablet.

  The size of the tablet is not particularly limited and can be appropriately determined in consideration of the blending amount and dose of the component (A). From the viewpoint of ease of tablet handling and swallowability, the tablet diameter is 5 to 14 mmφ. Is preferable, and 7 to 12 mmφ is more preferable. The tablet mass per tablet is suitably about 150 to 700 mg.

  The tablet of the present invention can be used as an antipyretic analgesic or a cold medicine, and is preferably an orally disintegrating tablet that disintegrates in the stomach from the viewpoint of ease of swallowing and exhibiting effectiveness.

EXAMPLES Hereinafter, although an Example , a reference example, and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example. In the following examples, unless otherwise specified, “%” in the composition represents mass%, and the ratio represents mass ratio. In the table, the mass ratio is 300 mg per tablet.

[Example 1-1 4, Reference Example 5, Comparative Examples 1 to 7]
(A) A poorly water-soluble non-steroidal anti-inflammatory agent (particles having an average particle size of 25 μm or less) is dry-mixed with (B) sucrose fatty acid ester, and then (C), (D), and (E) components are further blended. Dry-mixing was performed, and the mixture was tableted to obtain tablets. About the obtained tablet, disintegration and dissolution were evaluated by the following methods. The results are also shown in the table.

[Collapse]
According to the disintegration test method for tablets listed in the Japanese Pharmacopoeia (disintegration test solution is water), the disintegration time of 6 tablets was measured and the average value was determined. Based on the average value obtained, the disintegration property is shown based on the following evaluation criteria.
<Evaluation criteria>
◎: Collapse in less than 45 seconds ○: Collapse in 45 seconds to less than 1 minute Δ: Collapse in 1 minute to less than 2 minutes ×: Collapse in 2 minutes or more

[Dissolution]
The dissolution test was performed according to the paddle method listed in the Japanese Pharmacopoeia. The pH of the dissolution test solution was 4.5, the paddle rotation speed was 50 rpm, and the test solution was sampled over time to evaluate the time when the dissolution rate was 90%. Evaluation is performed 3 times, and the dissolution property is shown based on the average value.
<Evaluation criteria>
◎: Elution rate reaches 90% in less than 5 minutes ○: Elution rate reaches 90% in 5 minutes or more and less than 10 minutes Δ: Elution rate reaches 90% in 10 minutes or more and less than 30 minutes ×: Elution rate 90 30% or more to reach%

  In the tablet obtained by dry-mixing the component (A) and the component (B) in advance, blending the components (C) to (E) with the obtained dry mixture and mixing, and then compressing the mixture Both disintegration and dissolution were excellent. In particular, when the HLB grade of sucrose stearate was 11 or more, both disintegration and dissolution were excellent. Moreover, both the disintegration property and the dissolution property were excellent when the blending ratio of the component (A) and the component (B) was in the range of (B) / (A) = 0.03 to 0.4. On the other hand, as shown in the comparative example, when any of the components (B), (C), (D), and (E) was not included, it was not possible to achieve both disintegration and dissolution. Moreover, when it deviated from the range of (A) / (B) = 0.03 to 0.4, it was not possible to achieve both disintegration and dissolution.

[Examples 15 to 17 ]
(A) Ibuprofen (particles having an average particle size of 25 μm or less) was used as a component, and (B) dry-mixed with sucrose fatty acid ester (dry-mixing), and ibuprofen was melt-granulated with sucrose fatty acid ester (melt-granulation). , Lee Bupurofen was stirred granulated sucrose fatty acid ester (wet granulation). (C), (D), and (E) component were mix | blended with the obtained thing, and compression granulation (dry granulation) was carried out with the roller compactor. After the compressed granulated product was sized, the compressed granulated product and lactose were mixed, and the mixture was tableted. About the obtained tablet, the disintegration property and the dissolution property were evaluated by the above methods. All tablets showed excellent disintegration and dissolution properties.

[Examples 18 to 22, Reference Example 6 ]
(B) Component sucrose stearate is selected as component (B), dry blended, and then components (C), (D) and (E) are blended. Then, compression granulation (dry granulation) was performed with a roller compactor. After the compressed granulated product was sized, the compressed granulated product and lactose were mixed, and the mixture was tableted. About the obtained tablet, the disintegration property and the dissolution property were evaluated by the above methods. All tablets showed excellent disintegration and dissolution properties. The average particle size of ibuprofen used is as shown in the table.

[Examples 23 and 24 ]
The components (A) to (E) were simultaneously dry mixed, and the mixture was tableted to obtain tablets. About the obtained tablet, the disintegration property and the dissolution property were evaluated by the above methods. Although any of the tablets showed excellent disintegration and dissolution properties, Example 1 in which the components (A) and (B) were separately dry-mixed in advance had slightly better dissolution properties.

[Examples 25 to 27, Reference Example 7 ]
As shown in the following table, tablets were prepared by changing the ratio of the component (C) to the component (A). Specifically, after the components (A), (B) and (C) are dry-mixed, the components (D) and (E) are blended into the resulting dry mixture, and compression granulation (dry-type) is performed with a roller compactor. Granulation). After the compressed granulated product was sized, the compressed granulated product and lactose were mixed, and the mixture was tableted. About the obtained tablet, the disintegration property and the dissolution property were evaluated by the above methods. Although any tablet exhibited excellent disintegration and dissolution properties, the disintegration and dissolution properties were particularly excellent when (C) / (A) was 0.01 or more. However, in Example 27 , although disintegration and dissolution were excellent, there were a lot of fine powders and there was some difficulty in handling.

[Examples 28-30 , Reference Example 8 ]
As shown in the following table, tablets were prepared by changing the ratio of the component (D) to the component (A). Specifically, the components (A), (B), and (C) were dry mixed, the components (D) and (E) were blended, and compression granulation (dry granulation) was performed with a roller compactor. After the compressed granulated product was sized, the compressed granulated product and lactose were mixed, and the mixture was tableted. About the obtained tablet, the disintegration property and the dissolution property were evaluated by the above methods. Although any tablet exhibited excellent disintegration and dissolution properties, the disintegration and dissolution properties were particularly excellent when (D) / (A) was 0.5 or more.

[Examples 31 to 33, Reference Examples 9 and 10 ]
As shown in the following table, tablets were prepared by changing the ratio of the component (E) to the component (A). Specifically, the components (A), (B), and (C) were dry mixed, the components (D) and (E) were blended, and compression granulation (dry granulation) was performed with a roller compactor. After the compressed granulated product was sized, the compressed granulated product and lactose were mixed, and the mixture was tableted. About the obtained tablet, the disintegration property and the dissolution property were evaluated by the above methods. Although any tablet exhibited excellent disintegration and dissolution properties, the disintegration properties and dissolution properties were particularly excellent when (E) / (A) was 0.05 to 0.1.

[Examples 34 to 36 ]
As shown in the following table, (A) to (E) were selected, and bromhexine hydrochloride, clemastine fumarate, and acetaminophen were selected as other components, and dry granulation was performed. The obtained dry granulated granules were mixed with dry aluminum hydroxide gel, anhydrous caffeine, crystalline cellulose, carboxymethyl cellulose, and magnesium stearate in the proportions shown in the table below, and the mixture was tableted. About the obtained tablet, the disintegration property and the dissolution property were evaluated by the above methods. All tablets exhibited excellent disintegration and dissolution properties.

Claims (7)

(A) one or more selected from ibuprofen, ketoprofen and naproxen ;
(B) a sucrose fatty acid ester having a freezing point of 30 ° C. or higher and an HLB of 13 or higher;
(C) a compound selected from light anhydrous silicic acid, hydrous silicon dioxide and sodium stearyl fumarate;
(D) a compound selected from crystalline cellulose, silicified crystalline cellulose and powdered cellulose;
(E) a disintegrating agent, the average particle size of the component (A) is 50 μm or less, and the mass ratio of the component (A) and the component (B) represented by (B) / (A) is , 0.0 4-0. 27 der is, the content weight ratio of the (C) / represented by (A) (A) component (C) is 0.005 to 0.1, with (D) / (A) The mass ratio of the component (A) and the component (D) represented is 0.22 to 5.0, and the components (A) and (E) represented by (E) / (A) The content mass ratio of the tablet is 0.03-0.17. Component (B), sucrose stearate, tablet of claim 1 Symbol placement is sucrose fatty acid ester selected from sucrose palmitate and sucrose myristate. (A) an average particle diameter of the component, the tablets according to claim 1 or 2 Symbol mounting, characterized in that at 25μm or less. (E) component, low-substituted hydroxypropylcellulose, carmellose, croscarmellose sodium, crospovidone, of any one of claims 1 to 3 is a disintegrating agent selected from sodium carboxymethyl starch and carmellose calcium tablet. The components (A) and (B) are dry-mixed in advance, the components (C) to (E) are blended and mixed in the obtained dry mixture, and the mixture is tableted. The manufacturing method of the tablet of any one of 1-4 . (A) component and (B) component are dry-mixed beforehand, (C)-(E) component is mix | blended with the obtained dry-type mixture, and after dry-granulating, this dry-granulated material is tableted. The manufacturing method of the tablet of any one of Claims 1-4 characterized by the above-mentioned. After the (A) component and the (B) component are previously melt granulated, wet granulated or co-ground, and then the components (C) to (E) are blended into the resulting product, followed by dry granulation The method for producing a tablet according to any one of claims 1 to 4 , wherein the dry granulated product is tableted.