JP2010168287A - Tablet for internal use - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a tablet for an internal use, which contains an ingredient selected from acetaminophen, allyl isopropyl acetyl urea and anhydrous caffeine, and has excellent collapsibility. <P>SOLUTION: This tablet for the internal use, is characterized by having a medicine layer comprising a mixture containing (A) an ingredient selected from acetaminophen, allyl isopropyl acetyl urea and anhydrous caffeine, (B) dry aluminum hydroxide gel and (C) an ingredient selected from low substituted hydroxypropyl cellulose and croscarmellose sodium. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to an internal tablet having excellent disintegration properties.

  Those with headaches expect immediate effect on antipyretic analgesics. However, many commonly used antipyretic analgesics such as aspirin, acetaminophen, anhydrous caffeine, allyl isopropyl acetylurea, and ibuprofen are poorly water-soluble. It was a problem.

  In order for a solid preparation to exert its medicinal effects, it is generally necessary for the active ingredient contained therein to be absorbed from the digestive tract, and as a previous step, the solid preparation must disintegrate and dissolve. Until now, various attempts have been made to improve the disintegration property of solid preparations. The most commonly practiced method is to incorporate a swelling substance such as starch into the preparation as a disintegrant. Such a swellable substance increases the volume by swelling with water, destroys the internal structure of the solid preparation, and promotes disintegration. As such a disintegrant, for example, corn starch, hydroxypropyl starch, sodium carboxymethyl starch, crystalline cellulose, carmellose, carmellose calcium and the like are commonly used. In addition, a technique for increasing the wettability of a solid preparation with water by using a surfactant that increases the amount of a disintegrant in order to improve the disintegration of a tablet containing an active ingredient is also known. However, with these technologies, the amount of the active ingredient in the tablet decreases, so the tablet becomes larger, resulting in problems such as reduced dosage, and problems such as reduced tablet hardness and increased costs due to complicated manufacturing processes. May occur. In addition, the pharmaceutical disintegration achieved by the conventional techniques as described above is still not fully satisfactory, and in order to achieve a higher pharmaceutical preparation disintegration of a solid preparation, further useful technology has been developed. It was desired.

JP 2005-139168 A JP 2008-74790 A JP 2001-122769 A JP-A-5-294829 JP 2002-87965 A

  Ingredients selected from acetaminophen, allyl isopropyl acetylurea and anhydrous caffeine are active ingredients that are particularly bad in disintegration when formed into a solid preparation. Accordingly, an object of the present invention is to provide a tablet for internal use containing an ingredient selected from acetaminophen, allylisopropylacetylurea and anhydrous caffeine and having excellent disintegration properties.

  As a result of intensive studies to achieve the above object, the present inventors have found that (A) a component selected from acetaminophen, allylisopropylacetylurea and anhydrous caffeine, (B) a dried aluminum hydroxide gel, and (C ) By using a component selected from low-substituted hydroxypropylcellulose and croscarmellose sodium in the same layer, disintegration that has not been obtained in the past and disintegration after storage can be obtained and transported. The present inventors have found that a tablet having tablet hardness that can withstand manufacturing and storage can be secured, and have made the present invention.

Accordingly, the present invention provides the following tablets for internal use.
[1]. (A) a component selected from acetaminophen, allylisopropylacetylurea and anhydrous caffeine, (B) a dried aluminum hydroxide gel, and (C) a component selected from low-substituted hydroxypropylcellulose and croscarmellose sodium A tablet for internal use comprising a drug layer made of a mixture containing
[2]. The tablet for internal use according to [1], comprising the drug layer and an aspirin-containing layer containing aspirin.
[3]. [1] or [2], wherein in the drug layer, the mass ratio of the component (B) and the component (C) represented by (C) / (B) is 0.05 to 2 Tablets for internal use.
[4]. In the drug layer, the mass ratio of the components (A), (B) and (C) represented by ((B) + (C)) / (A) is 0.07 to 0.81 The tablet for internal use in any one of [1]-[3].
[5]. Content of (A) component in a drug layer is 55-93 mass%, The tablet for internal use in any one of [1]-[4] characterized by the above-mentioned.
[6]. [1] to [5], wherein in the drug layer, the mass ratio of the component (A) and the component (B) represented by (B) / (A) is 0.02 to 0.8. ] The tablet for internal use in any one of.
[7]. In the drug layer, the component (A) having a particle size of 500 μm or less is 90% by mass or more with respect to the total component (A), and the component (B) has a particle size of 100 μm or less (B) It is 90 mass% or more with respect to the whole component, The tablet for internal use in any one of [1]-[6] characterized by the above-mentioned.

  ADVANTAGE OF THE INVENTION According to this invention, the tablet for internal use which contains the component chosen from a cetaminophen, allyl isopropyl acetyl urea, and anhydrous caffeine and has the outstanding disintegration can be provided.

Hereinafter, the present invention will be described in detail.
The tablet for internal use of the present invention comprises (A) a component selected from acetaminophen, allylisopropylacetylurea and anhydrous caffeine, (B) dry aluminum hydroxide gel, and (C) low-substituted hydroxypropylcellulose and cloth. It is a tablet for internal use which has a drug layer consisting of a mixture containing a component selected from carmellose sodium.

Component (A) The component (A) is a component selected from acetaminophen, allylisopropylacetylurea and anhydrous caffeine, and can be used alone or in combination of two or more. Acetaminophen is one of antipyretic analgesic components and is used as one of the main components of antipyretic analgesics that suppress symptoms such as fever and headache. Anhydrous caffeine is a drug used for antipyretic analgesics and cold medicines to assist analgesic effects. Allylisopropylacetylurea has hypnotic / sedative effects and is a commonly used drug for antipyretic analgesics and cold medicines for the purpose of assisting analgesic effects. Acetaminophen is preferably coated acetaminophen coated with hydroxypropyl cellulose (recorded in the 15th revised Japanese Pharmacopoeia) from the viewpoint of capping prevention.

(B) component (B) component is a dry aluminum hydroxide gel and is an antacid drug of a Japanese collection. Dry aluminum hydroxide gel is known as an antacid that controls the pH of the stomach. However, dry aluminum hydroxide gel, which is an antacid, contains acetaminophen, anhydrous caffeine, or allylisopropylacetylurea as an active ingredient when used in combination with component (C), which is a specific disintegrant described later. It is a new finding of the present inventor that the tablet (hereinafter referred to as a tablet containing the component (A)) specifically has the effect of improving disintegration of a specific active ingredient.

Component (C) The component (C) is a component selected from low-substituted hydroxypropylcellulose and croscarmellose sodium, and can be used singly or in appropriate combination of two or more. By using low-substituted hydroxypropylcellulose (recorded in the 15th revised Japanese pharmacopoeia, hydroxypropoxyl group 5.0 to 16.0 mass%), croscarmellose sodium (recorded in the 15th revised Japanese pharmacopoeia), Disintegration of the tablet containing the component (A) of the present invention can be remarkably improved. Tablets containing the component (A) cannot achieve sufficient disintegration with other disintegrants, and the desired disintegration can be obtained by combining the components (B) and (C). The low-substituted hydroxypropylcellulose is distinguished from hydroxypropylcellulose (recorded in the 15th revised Japanese Pharmacopoeia, hydroxypropoxyl group 53.4-77.5 mass%).

The compounding ratio of the components (A), (B) and (C) in the drug layer is preferably in the following range from the viewpoint of exhibiting excellent disintegration properties.
The mass ratio of component (C) to component (B), that is, the mass ratio represented by (C) / (B) is preferably in the range of 0.05 to 2, and more preferably in the range of 0.1 to 1. The total content of the component (B) and the component (C) in the drug layer is preferably 3 to 55% by mass, more preferably 5 to 50% by mass, and particularly preferably 7 to 35% by mass.

  In addition, the mass ratio of the sum of the (B) component and the (C) component to the (A) component, that is, the mass ratio represented by ((B) + (C)) / (A) in the drug layer is 0. It is preferably 07 to 0.81, and more preferably 0.09 to 0.48. Moreover, 55-93 mass% is preferable, and, as for content of (A) component in a drug layer, 67-91 mass% is more preferable.

  Furthermore, the mass ratio of the component (B) to the component (A), that is, the mass ratio represented by (B) / (A) in the drug layer is 0.02 to 0.8 from the viewpoint of disintegration. Preferably, 0.04 to 0.44 is more preferable.

  The particle size of the components (A) to (C) used in the present invention can be arbitrarily set within the range where there is no problem in manufacturability, but the particle size of the component (A) is 500 μm or less in the entire component (A). On the other hand, it is 90% by mass or more, preferably 95 to 100% by mass, and the particle size of the component (B) is 100 μm or less, and 90% by mass or more, preferably 95 It is preferable that it is 100 mass%. By setting the particle sizes of the component (A) and the component (B) within this range, a tablet having excellent mixing uniformity and no tableting trouble such as binding can be produced. The sieves used for the measurement are those having an opening of 850, 710, 500, 355, 250, 150, 100 μm, and are calculated by vibrating for 5 minutes using M-2 type manufactured by Tsutsui Rika Instruments Co., Ltd.

  Further, the ratio of the low-substituted hydroxypropylcellulose component (C) having a particle size of 50 μm or less is preferably 90% by number or more, and the ratio of the croscarmellose sodium particle size of 200 μm or less is preferably in the range of 95% by number or more. . The upper limit is not particularly limited, but may be 100% by number. The measurement is performed with a laser diffraction particle size distribution analyzer (SALD-2200, manufactured by Shimadzu Corporation).

  You may mix | blend an additive arbitrarily with a drug layer in the range which does not impair the physical property of (A) component, and storage stability. Examples of additives include binders, excipients other than the component (C), lubricants, fragrances, flavoring agents (sweeteners, acidulants, etc.), pigments, stabilizers, and the like. Or an appropriate amount can be used in combination of two or more.

  Specifically, starch, pregelatinized starch, sucrose, gelatin, gum arabic powder, methylcellulose, polyvinylpyrrolidone, pullulan, dextrin and the like can be used as the binder. As the excipient, lactose, corn starch, talc, crystalline cellulose (such as thesaurus), powdered sugar, mannitol, light anhydrous silicic acid, calcium carbonate, L-cysteine, magnesium carbonate, magnesium oxide, magnesium aluminate metasilicate, etc. are used. be able to. Examples of the lubricant include magnesium stearate, calcium stearate, polyethylene glycol, talc, stearic acid, and sucrose fatty acid ester. 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.

  The tablet for internal use of the present invention has a drug layer composed of a mixture containing the components (A), (B) and (C), and is not particularly limited as long as it has such a drug layer. It may be a layer or a multilayer. In the case of a single-layer tablet, only the drug layer is present, and when it has layers other than the drug layer, it becomes a multilayer tablet having two or more layers. Thus, the objective excellent disintegration property can be obtained by setting it as the mixture containing the said (A), (B) and (C) component in the same layer.

  The layers other than the drug layer in the multilayer tablet are not particularly limited as long as the composition is different from that of the drug layer. For example, a multilayer tablet having the drug layer and an aspirin-containing layer containing aspirin can be obtained. By blending aspirin, a further excellent antipyretic analgesic effect can be expected. Moreover, it can also be expected that aspirin and the drug layer can be separated from each other by avoiding contact between aspirin and the components (B) and (C).

  Although the quantity of aspirin is not specifically limited, 40-60 mass% is preferable with respect to the whole tablet, and 80-100 mass% is preferable with respect to the whole aspirin containing layer.

  It is preferable to mix | blend an excipient | filler with an aspirin content layer from the disintegration point of an aspirin layer. Examples of excipients include lactose, corn starch and other starches, talc, crystalline cellulose (theolus, etc.), powdered sugar, mannitol, light anhydrous silicic acid, etc., and these may be used alone or in combination of two or more. Can do. Among these, lactose, starch, and mannitol are preferable, and starch is particularly preferable. As for content of an excipient | filler, 1-30 mass% is preferable with respect to the whole aspirin content layer. By combining a drug layer excellent in disintegrability and an aspirin-containing layer, disintegration as a whole tablet is improved, and as a result, an effect as a good pharmaceutical product can be expected.

  Furthermore, you may mix | blend an additive arbitrarily with the aspirin content layer of this invention in the range which does not impair a physical property, storage stability, and manufacturability. Examples of additives include binders, fragrances, flavoring agents (sweeteners, acidulants, etc.), pigments, stabilizers, and the like, and a suitable amount may be used alone or in combination of two or more. it can. Specifically, starch, pregelatinized starch, sucrose, gelatin, gum arabic powder, methylcellulose, polyvinylpyrrolidone, pullulan, dextrin and the like can be used as the binder. Examples of the fragrances include menthol, limonene, and plant essential oils such as mint oil, mint oil, lychee oil, orange oil, and lemon oil. 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.

  Other than the drug layer and the aspirin-containing layer, other active ingredients, various additives (binders, excipients, lubricants, flavors, flavoring agents (sweeteners, acidulants, etc.), pigments, and stabilization One or more of these agents can be used in appropriate combination and blended in an appropriate amount, and specific examples include those described in the drug layer and the aspirin-containing layer.

  The tablet of the present invention can be obtained, for example, by mixing (A), (B), (C) and optional components as necessary, filling the mixture into a tableting machine, and tableting. In the case of a multilayer tablet, the above mixture and another composition, and in the case of an aspirin-containing layer, an aspirin-containing composition (powder) containing aspirin is laminated and filled in a tableting machine, and tableting is performed to obtain a multilayer tablet. can do. The tableting pressure is not particularly limited and is appropriately selected.

  The obtained tablets may be coated with a coating agent as necessary. As such a coating agent, it is preferable to select a coating agent that does not significantly impair the disintegration property intended by the present invention. 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 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. From the viewpoint of ease of tablet handling and swallowability, the tablet weight per tablet is suitably about 225 mg to 700 mg.

  EXAMPLES Hereinafter, although an 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.

[Examples 1 to 28, Comparative Examples 1 to 36]
Each component shown in Tables 1 to 7 was blended based on the following production method to obtain a coated tablet having the composition shown in the table (however, the coating agent was excluded).
Hydroxypropylcellulose is dissolved in purified water and sprayed with a fluidized bed granulator (Freund Corporation: SFC-5 type) so that 2% of hydroxypropylcellulose adheres to acetaminophen, and granulated. did. The obtained acetaminophen granulated product (the proportion of particles having a particle size of 500 μm or less is 97.4% or more) is mixed with anhydrous caffeine, allylisopropylacetylurea, dry aluminum hydroxide gel (the proportion of particles having a particle size of 100 μm or less). 96.4%), Bore container mixer (Kotobuki Giken Kogyo Co., Ltd.) with magnesium aluminate metasilicate, magnesium oxide or carbonate, low-substituted hydroxypropylcellulose, croscarmellose sodium, carmellose calcium, sodium carboxymethyl starch or crospovidone For 20 minutes.
After primary mixing, magnesium stearate was added and mixed for another 10 minutes. The obtained mixed powder was tableted using a tableting machine (manufactured by Kikusui Seisakusho: Libra) to obtain an uncoated tablet.
Except for Examples 21 and 22 and Comparative Examples 29 to 32, the above mixed powder and aspirin, starch, and mixture were stacked and filled in a tableting machine, and tableted to obtain uncoated tablets.
1000 g of the obtained uncoated tablet was taken, a film coating agent (Opadry 03F48936: manufactured by Nippon Colorcon Co., Ltd.) composed of hydroxypropylmethylcellulose (HPMC) and a plasticizer was dissolved in water, and a 12% solution was used as a coating solution. The coating agent was sprayed so that it might become 1.0% with respect to the whole tablet, and the coated tablet was obtained. The following disintegration test was performed on the obtained coated tablets.

[Disintegration test]
According to the tablet disintegration test method listed in the 15th Japanese Pharmacopoeia, the disintegration time of 6 tablets was measured, and the average value was determined. A result is shown on the following reference | standard from an average value.
<Disintegration criteria>
◎: Disintegrates in less than 1 minute ○: Disintegrates in 1 minute or more and less than 3 minutes Δ: Disintegrates in 3 minutes or more and less than 10 minutes ×: Does not disintegrate even after 10 minutes or more

[Measuring method of particle size]
The particle size of the powder was determined by the sieving method for acetaminophen, anhydrous caffeine, allyl isopropyl acetyl urea, and dry aluminum hydroxide gel (the sieve used for the measurement had an opening of 850, 710, 500, 355, 250, 150). , Calculated by vibrating for 5 minutes using M-2 type manufactured by Tsutsui Rika Instruments Co., Ltd., and low-substituted hydroxypropylcellulose and croscarmellose sodium for the laser diffraction formula The particle size distribution was measured with a particle size distribution analyzer (SALD-2200, manufactured by Shimadzu Corporation). About the sieving method, the ratio was computed by the mass%. For the laser diffraction method, the ratio was calculated by number%.

  As shown in Examples 1 and 2, when (B) dry aluminum hydroxide gel, (C) low-substituted hydroxypropylcellulose or croscarmellose sodium is added to component (A), both the drug layer and the entire tablet are excellent. Showed disintegration. On the other hand, as shown in Comparative Examples 1 to 10, when the components (B) and (C) were not blended at the same time, excellent disintegration property was not exhibited. Moreover, as shown in Comparative Examples 11 to 28, when disintegrants other than excipients such as magnesium aluminate metasilicate and component (C) were selected, none of them exhibited excellent disintegration properties.

  The particle diameter of the component (A) used in the present invention is 97.4% by mass with a ratio of 500 μm or less, and the particle diameter of the dry aluminum hydroxide gel of the component (B) is 96.4 with a ratio of 100 μm or less. The particle size of the low-substituted hydroxypropyl cellulose of component (C) is 96.9% by number, and the particle size of croscarmellose sodium is 95.0% by number, 200μm or less. there were. By setting the particle size within this range, it was possible to obtain a tablet excellent in manufacturability free of capping and binding tableting troubles.

  Further, the tablets shown in Examples 1 and 2 and Comparative Examples 1 to 28 were stored at an air temperature of 40 ° C. and a humidity of 75%, and the disintegration property after 60 days was evaluated, but the tablets shown in Comparative Examples 1 to 28 were further disintegrated. Despite the time delay, the tablets of Examples 1 and 2 had no change in disintegration.

  As shown in Examples 3 to 20, the drug layer exhibited excellent disintegration when the ratio of the component (C) to the component (B) was 0.05 to 2.

  Furthermore, the tablets shown in Examples 3 to 20 were stored at an air temperature of 40 ° C. and a humidity of 75%, and the disintegration property after 60 days was evaluated. None of the tablets was changed in disintegration property.

  Furthermore, the tablets shown in Examples 21 to 28 were stored at an air temperature of 40 ° C. and a humidity of 75%, and the disintegration property after 60 days was evaluated, but none of the tablets changed in disintegration property.

The raw materials used in the above examples are shown below.
Aspirin starch mixture: Rhodia (Rhodine 2312): 90% by mass of aspirin, 10% by mass of corn starch
Acetaminophen: Anhydrous caffeine manufactured by Iwaki Pharmaceutical Co., Ltd .: Allyl isopropyl acetylurea manufactured by Shizuoka Caffeine Industry Co., Ltd .: Kongo Chemical Co., Ltd. (aripronal)
Dry aluminum hydroxide gel: manufactured by Kyowa Chemical Industry Co., Ltd. (dry aluminum hydroxide gel S100)
Hydroxypropyl cellulose: Nippon Soda Co., Ltd. (HPC-L)
Low substituted hydroxypropyl cellulose: manufactured by Shin-Etsu Chemical Co., Ltd. (LH-31)
Croscarmellose sodium: manufactured by Asahi Kasei Corporation (Kickolate ND-2SH)
Magnesium stearate: Taihei Chemical Industrial Co., Ltd. Magnesium metasilicate aluminate: Fuji Chemical Co., Ltd. (Neusilin US2)
Magnesium oxide: Tomita Pharmaceutical Co., Ltd. Magnesium carbonate: Tomita Pharmaceutical Co., Ltd. Carmellose calcium: Gotoku Pharmaceutical Co., Ltd. (ECG-505)
Sodium carboxymethyl starch: DMV international (Primojel)
Crospovidone: BASF (Kollidon CL)

Claims (7)

  (A) a component selected from acetaminophen, allylisopropylacetylurea and anhydrous caffeine, (B) a dried aluminum hydroxide gel, and (C) a component selected from low-substituted hydroxypropylcellulose and croscarmellose sodium A tablet for internal use comprising a drug layer made of a mixture containing   The tablet for internal use according to claim 1, comprising the drug layer and an aspirin-containing layer containing aspirin.   The mass ratio of the component (B) and the component (C) represented by (C) / (B) in the drug layer is 0.05 to 2, Taking tablets.   In the drug layer, the mass ratio of the components (A), (B) and (C) represented by ((B) + (C)) / (A) is 0.07 to 0.81 The tablet for internal use of any one of Claims 1-3.   Content of (A) component in a drug layer is 55-93 mass%, The tablet for internal use of any one of Claims 1-4 characterized by the above-mentioned.   The mass ratio of the component (A) and the component (B) represented by (B) / (A) in the drug layer is 0.02 to 0.8. The tablet for internal use of any one of Claims 1.   In the drug layer, the component (A) having a particle size of 500 μm or less is 90% by mass or more with respect to the total component (A), and the component (B) has a particle size of 100 μm or less (B) It is 90 mass% or more with respect to the whole component, The tablet for internal use of any one of Claims 1-6 characterized by the above-mentioned.