JP2007051133A - Tablet composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a tablet which has low hardness facilitating chew and swallowing in oral cavities, but has low friability and sufficient strength on handles. <P>SOLUTION: The compression-molded tablet comprises a medium chain fatty acid triglyceride having a freezing point of -30 to 15°C in an amount of 3 to 10 wt.% based on the total amount of the tablet, and has a hardness of 5 to 50 N. Preferably, the compression-molded tablet preferably further comprises a sugar alcohol. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a tablet having a sufficient strength in handling, having a low hardness for facilitating chewing and swallowing in the oral cavity, and having a low friability and few cracks and chips.

  Chewable tablets that are disintegrated or dissolved by chewing or the like in the oral cavity are convenient to carry because they can be taken without water, and have the advantage that they can be taken without trouble. However, general chewable tablets have high hardness and are not easy to chew for elderly people or patients with physical disabilities that make chewing difficult. Moreover, even if it is not an elderly person etc., in general, a tablet having a lower hardness than a tablet having a higher hardness has a better feeling to be taken, so that it tends to be preferred by consumers.

  From such a point, it is considered to improve the chewability by lowering the hardness of the tablet. However, if the hardness is lowered, the chewability can be improved, but since the frequency of occurrence of wear, cracking and chipping of the tablet increases as the hardness decreases, a practically sufficient strength cannot be obtained. That is, the tablet is easily damaged or worn at various stages such as manufacturing, transportation, and medication, and when the tablet is broken or worn, the mass is reduced and it becomes difficult to take a necessary dose. For example, when a plurality of tablets are bottled, or are transported or moved by being packed in a portable container, it is difficult to ensure a certain quality and dose due to breakage and wear of the tablets. Further, in order to prevent breakage and wear of tablets having insufficient strength, if each tablet is individually packaged by a packaging method such as SP packaging or PTP packaging, the cost increases.

  So far, the development of tablets that combine the low hardness required to facilitate chewing and swallowing in the oral cavity and sufficient strength required in the manufacturing and distribution processes has been studied. It was.

  For example, Patent Document 1 contains a medicinal component, a saccharide, and solid polyethylene glycol having a melting point of 40 ° C. to 70 ° C., and the polyethylene glycol has interparticle crosslinking between the medicinal component and the saccharide. An oral-dissolving tablet having a formed porous structure is disclosed.

  Furthermore, Patent Document 2 contains a medicinal component, a saccharide, and a low melting point substance having a melting point of 40 ° C. to 90 ° C., and the low melting point substance forms an interparticle bridge between the medicinal component and the saccharide. An oral dissolution tablet having a porous structure is disclosed. Patent Document 3 also teaches that those having a melting point lower than 40 ° C. cannot be expected to have a desired effect, for example, when stored indoors, depending on the storage location, the low melting point substance may be remelted and the tablet characteristics may change. Has been made.

  On the other hand, medium-chain fatty acid triglycerides are liquid fatty oil substances that have been used in pharmaceutical preparations as plasticizers and the like, and are known to have a very low freezing point. By the way, in general, it has been considered that a liquid plasticizer can be blended in at most about 2% by weight when blended in a compression-molded tablet. For example, U.S. Patent No. 6,057,033 shows that too much plasticizer itself affects the compression properties of the tablet (for example, the plasticizer is liquid at times, so the use of too much plasticizer is Gives an excess of liquid), thus giving the teaching that the upper limit of the amount of plasticizer in the tablet should be 2% by weight.

  Thus, so far, no compression-molded tablet containing 3 to 10% by weight of medium-chain fatty acid triglycerides, which have a very low freezing point and can be used as a liquid plasticizer, has never been taught or suggested. Until now, such medium-chain fatty acid triglycerides have a low hardness required to facilitate chewing and swallowing in the oral cavity and sufficient strength required in the production and distribution process. There was no teaching or suggestion that it could be used beneficially for development.

Japanese Patent Laid-Open No. 11-33084 JP-A-11-35451 JP 58-32820 A

  In view of such conventional problems, the present invention has a low hardness that facilitates mastication and swallowing in the oral cavity, but on the other hand, it has a low degree of friability and is low in wear, cracking, chipping, etc. An object of the present invention is to provide a new and useful tablet having a sufficient strength.

  As a result of intensive investigations to solve the above problems, the present inventors have determined that a specific high proportion of 3 to 10% by weight of medium-chain fatty acid triglyceride having a very low freezing point of −30 ° C. to 15 ° C. with respect to the whole tablet. It was found that a tablet with sufficient strength in handling can be obtained with low hardness, but with low hardness, cracking, and chipping, and having sufficient strength in handling. .

Accordingly, the present invention provides the following.
(1) A compression-molded tablet containing 3 to 10% by weight of a medium chain fatty acid triglyceride having a freezing point of −30 ° C. to 15 ° C. with respect to the whole tablet and having a hardness of 5 to 50N.
(2) The compression molded tablet according to item (1), further containing a sugar alcohol.
(3) The compression molded tablet according to item (2), wherein the sugar alcohol has a critical relative humidity at 37 ° C. of 70% or more.
(4) The compression-molded tablet according to item (2) or (3), wherein the sugar alcohol is at least one selected from the group consisting of D-mannitol, xylitol, erythritol, maltitol, lactitol, and reduced palatinose. .
(5) The compression molded tablet according to any one of items (1) to (4), wherein the friability of the compression molded tablet is 1% or less.
(6) The compression-molded tablet according to any one of items (1) to (5), which is a chewable tablet.

  According to the present invention, it has a low hardness that makes it easy to chew and swallow in the oral cavity, but on the other hand, it has a low degree of friability and also has sufficient strength in handling such as less wear, cracks, and chipping of tablets. Useful tablets are provided. Since the tablet of the present invention has sufficient strength for handling, it is not always necessary to individually package each tablet by a packaging method such as SP packaging or PTP packaging. Therefore, the tablets of the present invention can be distributed and sold by filling a plurality of the packaging containers such as bottles and lighter-type portable containers together, which is advantageous in terms of cost.

  In addition, as shown in the following examples, according to the present invention, tablets having the desired hardness and strength can be easily obtained with a wide range of tableting pressures without strictly controlling the tableting pressure. be able to. Furthermore, the tablet of the present invention does not necessarily need to undergo freeze-drying and complicated production processes that have been conventionally useful for obtaining easily disintegrating tablets, and is a very simple method of simply compression-molding a composition in which components are mixed. Can be manufactured by simple operation. As described above, the tablet of the present invention is extremely useful in that it can be produced very simply.

  Hereinafter, the present invention will be described in detail. Throughout this specification, it should be understood that expression in the singular also includes the concept of the plural unless specifically stated otherwise. In addition, it is to be understood that the terms used in the present specification are used in the meaning normally used in the art unless otherwise specified.

As used herein, the term “medium chain fatty acid” refers to a saturated fatty acid represented by CH ₃ (CH ₂ ) _n COOH, wherein n = 4 to 10, preferably n = 6 to 8. Means things.

  The “medium chain fatty acid triglyceride” used in the present invention is also simply referred to as MCT (short for Medium Chain Acid Triglyceride), and is a triglyceride in which at least one of three fatty acids ester-bonded to glycerin is a medium chain fatty acid. Preferably, it refers to a triglyceride in which at least two of the three fatty acids ester-linked to glycerin are medium chain fatty acids, most preferably a triglyceride in which all three of the fatty acids ester-linked to glycerin are medium chain fatty acids.

  In the present invention, a triglyceride having only one kind of medium chain fatty acid ester-linked to glycerin (for example, a triglyceride having only chain-chain fatty acid ester-linked to glycerin) may be used, Triglycerides with multiple types of medium chain fatty acid ester-linked to glycerin (for example, triglycerides in which the medium-chain fatty acid ester-linked to glycerin is caprylic acid and capric acid (caprylic acid / capric acid) triglyceride) May be. Moreover, only one kind of medium chain fatty acid triglyceride may be used for the medium chain fatty acid triglyceride of the present invention, or a mixture of plural kinds of medium chain fatty acid triglycerides may be used.

  The medium-chain fatty acid triglyceride used in the present invention may be an extract from a natural product or a synthetic product. Commercially available products are also available for the medium-chain fatty acid triglycerides used in the present invention. For example, Kao Corporation (trade name: Coconut), Nisshin Science Co., Ltd. (trade name: ODO-L), Mitsuba Trading Co., Ltd. (Trade name: Miglyol), Nippon Oil & Fat Co., Ltd. (trade name: Panaceto), Higher Alcohol Industry Co., Ltd. (trade name: TCG-M), or Riken Vitamin Co., Ltd. (trade name: Actor) is there.

  The term “freezing point” refers to the temperature at which solidification of a liquid or gas begins, as can be generally understood by those skilled in the art. For example, it is easily measured by those skilled in the art by the freezing point measurement method included in the 14th revised Japanese Pharmacopoeia. Can be done. In the case of impurities and mixtures, the freezing point changes during the solidification process, so the melting point and the freezing point do not match, and it is generally known that the freezing point of a mixture or the like is slightly lower than the freezing point of a pure substance. In the case of a pure substance, the freezing point coincides with the melting point.

  The medium chain fatty acid triglyceride used in the present invention has a freezing point of -30 ° C to 15 ° C. More preferably, the medium chain fatty acid triglyceride used in the present invention has a freezing point of −20 ° C. to 10 ° C., more preferably −15 ° C. to 5 ° C., and particularly preferably −10 ° C. to 0 °. It has a freezing point of ° C., and most preferably has a freezing point of −8 ° C. to −2 ° C.

  The tablet of the present invention contains medium-chain fatty acid triglycerides within a range of 3 to 10% by weight based on the whole tablet. The content ratio of the medium-chain fatty acid triglyceride can be appropriately changed by those skilled in the art within the above-mentioned range depending on the kind and property of the medium-chain fatty acid triglyceride used. Preferably, the content of medium-chain fatty acid triglyceride in the whole tablet is 3 to 8% by weight, more preferably 3 to 7% by weight, and more preferably in the whole tablet. It is 3 to 6% by weight, particularly preferably 3 to 5% by weight based on the whole tablet.

  The tablet of the present invention is produced by a compression molding method. Usually, when a large amount of a liquid substance having a very low freezing point is contained in a tablet, the constituent components of the tablet adhere to the tablet punch (sticking), and it has been considered difficult to produce a tablet by a compression molding method. However, the present inventors have surprisingly found that even when a liquid medium chain fatty acid triglyceride having a remarkably low freezing point is blended at a high ratio as in the present invention, tableting can be performed smoothly and tablets can be easily produced. .

  Specifically, the tablet of the present invention includes the above-described medium chain fatty acid triglyceride and other optional components blended as necessary (for example, excipients blended to adjust the shape of the tablet, etc.). (But not limited to this), tablet blending components such as, but not limited to, are weighed and mixed, and then the mixture is directly compression-molded (direct compression method) or granulated into the mixture obtained as described above To produce a granulated product, and if necessary, the granulated product is sized to form a granule, and then the granulated product or granule is compression-molded (indirect compression method).

  As a method for mixing the tablet compounding components, any method known in the art that can stably and uniformly mix each tablet compounding component can be used. Most simply, for example, mixing can be performed using a mixer such as a container rotating mixer or a container fixed mixer.

  If necessary, before applying the compression molding process described below, the mixture thus obtained is granulated to produce a granulated product, or further subjected to a granulating process to produce a granulated product. To manufacture. Examples of granulation methods that can be performed to obtain the tablet of the present invention include, for example, extrusion granulation method, fluidized bed granulation method, tumbling granulation method, high-speed stirring granulation method, spray drying method, emulsion granulation Law, etc., but is not limited thereto. Examples of the sizing treatment method that can be performed to obtain the tablet of the present invention include, but are not limited to, a wet pulverization sizing method, a dry pulverization sizing method, and a roll pulverization method.

  In order to compression-mold the mixture, granulated product or granule obtained as described above, any compression molding apparatus known in the art can be used. Examples of the compression molding apparatus include, but are not limited to, a rotary tableting machine and a single-shot tableting machine. Preferably, compression molding is performed using a rotary tableting machine.

  In the present specification, the “hardness” of a tablet refers to the degree of force required to break the tablet, specifically, the force (unit: N) when the tablet is broken by applying a force in the diameter direction of the tablet. For example, as described in the following examples, it can be easily measured using a tablet breaking strength measuring instrument.

  The present inventors weighed and mixed the tablet compounding ingredients so as to contain 3 to 10% by weight of the medium chain fatty acid triglyceride having a freezing point of −30 ° C. to 15 ° C. When it is molded so that its hardness is in the range of 5 to 50 N, it becomes easy to chew and swallow in the oral cavity, a smooth texture is obtained, and a very good feeling of taking is obtained, but surprisingly In particular, it was found that the tablet was useful and had sufficient strength in handling because it had low friability and reduced tablet wear, cracking, and chipping.

  From the above, the tablet of the present invention has a hardness of 5 to 50N. The hardness of the tablet of the present invention can be any hardness as long as it is in the range of 5 to 50N. In certain embodiments, the lower limit of the hardness of the tablet of the present invention may be, for example, 10N or more, 12N or more, 15N or more, 20N or more, 25N or more, or 29N or more. It can be. Also, the upper limit of the hardness of the tablet of the present invention can be, for example, 48N or less, 45N or less, 40N or less, 35N or less, or 30N or less. The hardness of the tablet can be easily determined by a tablet hardness test or the like as described in the following examples.

  As long as the hardness of the tablet is within a range of 5N to 50N, any tableting pressure can be used as the tableting pressure for compression molding. A person skilled in the art can appropriately determine the tableting pressure necessary to obtain the desired hardness based on common general technical knowledge and empirical rules. Further, as shown in the following examples, according to the present invention, it is not necessary to strictly control the tableting pressure, and tablets having a hardness of 5 to 50 N with a relatively wide range of tableting pressures. Can be obtained. Preferably, the tableting pressure at the time of compression molding is 1 to 30 kN / 杵, more preferably 5 to 20 kN / 杵, and particularly preferably 5 to 15 kN / 杵.

  In the present specification, the “friability” of a tablet refers to a value indicating the wear and brittleness of a tablet against impact, and specifically, a tablet friability test method listed in the 14th revised Japanese Pharmacopoeia. , The tablet is placed in a transparent plastic drum type tester with an inner diameter of about 287 mm and a depth of about 38 mm, and the inner surface is smooth. After rotating 100 times at a rotation speed of 24 to 26 rotations per minute, It refers to a value determined by accurately measuring the mass of a tablet and calculating the mass percentage of the reduced mass relative to the initial mass.

  Despite having a low hardness, the tablets of the present invention are significantly less friable. In a preferred embodiment, the friability of the tablet of the present invention is 1% or less. More preferably, the friability of the tablet of the present invention is 0.8% or less, more preferably 0.7% or less, and particularly preferably 0.5% or less.

  The tablet of the present invention can take any form, but is preferably swallowable in the oral cavity by being chewed if necessary to disintegrate or dissolve (this form is referred to as “chewable tablet” in the present specification). ). Examples of chewable tablets include, but are not limited to, chewable tablets, intraoral quick disintegrating tablets, and intraoral quick dissolving tablets. Preferably, the tablet of the present invention is a chewable tablet.

  The tablet of the present invention may further contain a sugar alcohol. As shown in the examples below, it has been demonstrated that the tablet of the present invention can have sufficient strength in handling due to low friability even when the hardness of the tablet is significantly reduced by using sugar alcohol together. ing.

  The “sugar alcohol” used in the present invention refers to any polyhydric alcohol obtained by reducing the carbonyl group of a sugar molecule, and may be either D-form, L-form or DL-form. For example, the sugar alcohol can be mannitol, xylitol, erythritol, maltitol, lactitol, reduced palatinose (palatinite), sorbitol, and the like.

  The sugar alcohols D-mannitol, xylitol, and lactitol used in the examples are all known to have a critical relative humidity at 37 ° C. of 70% or more. Therefore, preferably, a sugar alcohol having a critical relative humidity at 37 ° C. of 70% or more is used in the present invention. The term “critical relative humidity” is a hygroscopic parameter well known in the art, also referred to as critical specific humidity, and indicates the inherent hygroscopicity of the substance of interest. A low critical relative humidity means that the substance has a property of easily absorbing moisture, and conversely, a high critical relative humidity means that the substance has a property of hardly absorbing moisture. Examples of sugar alcohols having a critical relative humidity at 37 ° C. of 70% or more include erythritol, xylitol, D-mannitol, maltitol, lactitol, and reduced palatinose. In the present invention, these sugar alcohols are preferably used. Can be used. More preferably, the sugar alcohol used in the present invention is erythritol, xylitol, D-mannitol, and / or lactitol.

  In the tablet of the present invention, only one kind of sugar alcohols as described above may be used, or two or more kinds may be used in combination.

  The sugar alcohol used in the present invention may be an extract from a natural product, a synthetic product, or a commercially available product. For example, commercially available sugar alcohols include Mitsubishi Chemical (trade name: erythritol), Towa Kasei Kogyo (trade name: Xylit, Mannit, Sorbit, Amarti, Resis, Milchen, etc.), Kao Corporation (trade name: Nippon Pharmacy) Higashi Mannitol Kao), Nikken Kasei Co., Ltd. (trade name: Lactitol Nikken), and the like.

  When the sugar alcohol is blended in the tablet of the present invention, the blending ratio with respect to the whole tablet is not particularly limited as long as the effects of the present invention can be achieved, and may be appropriately changed by those skilled in the art based on the type and nature of the sugar alcohol used. Can be done. Preferably, however, the content of sugar alcohol in the whole tablet is 30 to 97% by weight, preferably 40 to 90% by weight, particularly preferably 50 to 75% by weight, based on the whole tablet.

  The mixing ratio of the medium-chain fatty acid triglyceride and the sugar alcohol in the tablet of the present invention is not particularly limited as long as the effects of the present invention can be achieved, and those skilled in the art based on the types and properties of the medium-chain fatty acid triglyceride and sugar alcohol used. Depending on the situation. However, the sugar alcohol is preferably 3 to 32 parts by weight, more preferably 4 to 30 parts by weight, and particularly preferably 5 to 25 parts by weight with respect to 1 part by weight of the medium chain fatty acid triglyceride.

  Furthermore, the tablet of this invention may contain the other component as enumerated below as needed. Other components as described below may be blended alone or in combination of two or more. Other ingredients as listed below may also be in the form of their physiologically or pharmaceutically acceptable salts.

  Examples of components that can be blended as additional components include medicinal components (bioactive components, pharmacologically active components, or active components). These components are not particularly limited, and include, for example, antipyretic analgesic components (aspirin, salicylic acid derivatives such as methyl salicylate; acetaminophen, sazapyrine, ethenamide, isopropylantipyrine, indomethacin, ibuprofen, etc.), sedative hypnotic components (bromvalerylurea, Allylisopropylacetylurea), anti-inflammatory ingredients (celecoxib, lysozyme, azulene sulfonic acid, etc.), antihistamine ingredients (chlorpheniramine, mequitazine, diphenhydramine, etc.), antiallergic ingredients (emedastine, etc.), expectorant ingredients (potassium guaiacol sulfonate) , L-ethylcysteine hydrochloride, potassium cresol sulfonate, bromhexine hydrochloride, ambroxol hydrochloride, guaifenesin, etc., antitussive ingredients (Maou, Nantenjitsu) Any herbal medicine), bronchodilators (such as xanthine derivatives such as caffeine), parasympatholytic agents (such as belladonna alkaloids, belladonna total alkaloids), bactericidal ingredients (such as cetylpyridinium chloride, decalinium chloride, chlorhexidine hydrochloride), vasopressors (such as Phenylephrine hydrochloride, etc.), healthy stomach ingredients (herbs such as aniseed fruit and aloe); parasympathomimetic drugs such as carnitine; anti-dopamine drugs such as metoclopramide; trimebutine, menthol, glutamic acid, etc .; antacid components (magnesium carbonate, precipitated magnesium carbonate) , Dry aluminum hydroxide gel, histamine H2 receptor antagonist (such as cimetidine), proton pump inhibitor (such as lansoprazole)), mucosal repair component (such as glycyrrhizic acid or its salt), digestive component (diastase, Creatine, such as pepsin), cell-activating component (retinal, retinol, etc.), herbal components, vitamins, amino acids, such as minerals may be exemplified. The medicinal components can be used alone or in combination of two or more.

  The content of the medicinal ingredients as described above can be appropriately selected depending on the size and use of the tablet, and is, for example, 0.001 to 80% by weight, preferably 0.001 to 30% by weight, more preferably based on the whole tablet. May be 0.001 to 10% by weight.

  The tablet of the present invention can also be used as an ingredient other than the above-mentioned medicinal ingredients, as well as conventional ingredients used in quasi drugs, pharmaceuticals or foods, for example, sweeteners, flavoring agents, lubricants, disintegrants, binders. , Excipients, preservatives, chelating agents, antioxidants, cooling agents, coating agents, disintegration aids, stabilizers, suspending agents, fluidizing agents, emulsifying agents, thickening agents, thickening agents Agents, buffers, fragrances, colorants, dispersants, adsorbents, wetting agents, moisture-proofing agents, antistatic agents, foaming agents and the like may be contained. The preparation of the present invention particularly preferably contains a nonionic surfactant. In particular, in the embodiment of the present invention containing a medium-chain fatty acid triglyceride and a sugar alcohol, the disintegration of the preparation can be remarkably improved by further adding a nonionic surfactant. Examples of the nonionic surfactant include, but are not limited to, polyoxyethylene sorbitan fatty acid ester, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, and the like. Particularly preferably, the preparation of the present invention contains a polyoxyethylene sorbitan fatty acid ester (for example, polysorbate 80 (also known as polyoxyethylene sorbitan monooleate (20E.O.)), polysorbate 60 (also known as polyoxymonostearate). Ethylene sorbitan (20E.O.)) and polysorbate 20 (also known as polyoxyethylene sorbitan monolaurate (20E.O.)) are used.

  The content of components other than the medicinal components as described above can be appropriately selected depending on the size and use of the tablet, and is, for example, 0.001 to 97% by weight, preferably 0.01 to 0% based on the whole tablet. For example, it may be 90% by weight. For example, when a nonionic surfactant is added to the preparation of the present application for the reasons described above, the content of the nonionic surfactant is not particularly limited, but is 0.01 to It may be 10% by weight, preferably 0.1 to 5% by weight, more preferably 0.1 to 3% by weight.

  Furthermore, it has been clarified that the compression-molded tablet of the present invention masks bitterness significantly even when a component having bitterness is blended. This bitterness masking effect showed a marked difference compared to compression-molded tablets whose freezing point did not contain any medium chain fatty acid triglycerides at -30 ° C to 15 ° C. Therefore, a component having a bitter taste can be suitably blended in the tablet of the present invention. Examples of ingredients having a bitter taste include vinpocetine, fursultiamine, fursultiamine hydrochloride, cefcanel daloxate hydrochloride, cefotiam hexetyl hydrochloride, lenampicillin hydrochloride, bacampicillin hydrochloride, tarampicillin hydrochloride, pivemecillinam hydrochloride, oxerazine tannate, clobutycyl hydrochloride Nord, berberine hydrochloride, propateline bromide, papaverine hydrochloride, ticlopidine hydrochloride, chloropromazine hydrochloride, sultamicillin tosylate, anhydrous caffeine, caffeine, diprofilin, diphenhydramine salicylate, chlorpheniramine maleate, pyridoxine hydrochloride, dimenhydrinate, hydrochloric acid Meclizine, methylephedrine hydrochloride, potassium guaiacol sulfonate, guaifedin, chlorhexidine hydrochloride, dihydrocodeine phosphate, hydrochloric acid Fedrine, spironolactone, tegafur, erythromycin stearate, alacepril, sodium parproate, meclofenoxate hydrochloride, chloramphenicol, aminophylline, erythromycin, calcium hopatenate, calcium pantothenate, phenobarbital, cimetidine, ethylephrine hydrochloride, pirenzepine hydrochloride, Butylscopolamine hydrochloride, diltiamine hydrochloride, enoxacin, pyromido acid trihydrate, propranolol hydrochloride, flufenamic acid, chlorpromazine, digitoxin, promethazine hydrochloride, metoclopramide hydrochloride, ofloxacin, sulpyrine, acetaminophen, aspirin, ibuprofen, pendidamine hydrochloride, alpreno hydrochloride Roll, Bifemelane hydrochloride, Lidocaine, Diphenhydramine hydrochloride, Tolu Chin sodium, nortriptyline hydrochloride, loperamide hydrochloride, azelastine hydrochloride, bifemelane hydrochloride, quinidine sulfate, S-(+)-(2-chlorophenyl) -3-cyclopropanecarbonyl-8, 11-dimethyl-2, 3, 4, 5- Tetrahydro-8H-pyrido- [4,3: 4,5] thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine, (+)-( 5R, 6S) -6-[(R) -1-hydroxyethyl] -3- (3-pyridyl) -7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene- Examples include 2-carboxylic acid acetoxymethyl ester, but are not limited thereto.

  The content of the component having a bitter taste as described above can be appropriately selected depending on the size and use of the tablet, and is, for example, 0.001 to 30% by weight, preferably 0.001 to 20% by weight, based on the whole tablet. More preferably, it may be 0.01 to 10% by weight.

  The tablet can be appropriately selected in size and shape for easy internal use, and may be an uncoated tablet, or may be coated with a film coat base, sugars, sugar alcohols, or the like.

  The tablet of the present invention can be packaged in any packaging form. For example, the packaging form may be a form in which each tablet is individually packaged, such as SP packaging or PTP packaging, or a bottle or container of any shape / use (for example, a lighter-type portable container). The package may take a form in which a plurality of tablets are packed together. The latter form in which a plurality of tablets are packed together and filled into a package is advantageous in terms of cost and is preferable. The package may be made of any material, and for example, may be made of glass or plastic, but is not limited thereto.

  The tablet of the present invention is a pharmaceutical, quasi-drug, food (for example, food for the aged, food for special use, food for specified health use, nutritional functional food, functional food, health supplement, supplement, health food, confectionery, confectionery. , Animal food, pet food, feed) and the like. Moreover, the tablet of this invention can be utilized as pharmaceuticals of arbitrary uses, such as a rhinitis drug, a motion sickness drug, a gastrointestinal drug, and an antidiarrheal drug. Particularly preferably, the tablet of the present invention can be suitably used as a tablet that can be taken without water.

  EXAMPLES The present invention will be described in detail below based on examples, but the present invention is not limited to these examples.

Example 1:
(Preparation of test tablets)
The test tablet of this example was prepared by the following method.
First, 6 parts by weight of d-chlorpheniramine maleate, 0.4 parts by weight of total belladonna alkaloids, 60 parts by weight of anhydrous caffeine, 15 parts by weight of phenylephrine hydrochloride, 21 parts by weight of aspartame, 190 parts by weight of corn starch, 27 parts of hydroxypropylcellulose Parts by weight, and 439.6 parts by weight of D-mannitol are mixed in advance, and an appropriate amount of ethanol is added thereto and kneaded to obtain a medium chain fatty acid triglyceride ((caprylic acid / capric acid) triglyceride, freezing point: about −5 ° C.) 36 After being dispersed in parts by weight, it was granulated by an extrusion granulation method. This granulated product is sized and granulated, and then 75 parts by weight of light anhydrous silicic acid and 30 parts by weight of magnesium stearate are added to the granule, using a V-type mixer (manufactured by Tokuju Kogakusho Co., Ltd.). Mix for 15 minutes. This mixture was tableted with a rotary tableting machine (Collect 19, manufactured by Kikusui Seisakusho Co., Ltd.) at a tableting pressure of 9.8 kN / kg to obtain a circular tablet (diameter 9.5 mm, one tablet 300 mg).

  The obtained test tablets were examined for tablet hardness and friability according to the following method.

(Tablet hardness test)
Ten tablets collected arbitrarily from the obtained test tablets were pressed in the tablet diameter direction with a tablet breaking strength measuring instrument (Toyama Sangyo Co., Ltd., tablet breaking strength measuring instrument TH203 type) according to a conventional method. The degree of force (N) when the tablet was broken was measured, and the average measured value was taken as the hardness. As a result, the hardness of this test tablet was 26.5N.

(Tablet friability test)
The test was conducted in accordance with the friability test method for tablets listed in the 14th revised Japanese Pharmacopoeia. That is, the total mass (initial mass) of 19 test tablets is precisely weighed, and the tablets are placed in a plastic drum-type tester having an inner diameter of about 287 mm and a depth of about 38 mm, and a smooth inner surface. 100 rotations were performed at a rotation speed of 1 minute. After the end of rotation, the mass of all tablets was measured accurately, and the friability (mass percentage of the reduced mass with respect to the initial mass) was determined. The results showed that the friability of this test tablet was only 0.25%.

Example 2:
The test tablet of this example was prepared by the following method.
First, 0.5 parts by weight of scopolamine hydrobromide, 12 parts by weight of pyridoxine hydrochloride, 50 parts by weight of meclizine hydrochloride, 250 parts by weight of corn starch, 906.86 parts by weight of xylitol, 36 parts by weight of hydroxypropyl cellulose, 30 parts by weight of aspartame, And 1.44 parts by weight of a fragrance are mixed in advance, and an appropriate amount of ethanol is added thereto and kneaded to obtain a medium chain fatty acid triglyceride ((caprylic acid / capric acid) triglyceride, freezing point: about −5 ° C.) at 43.2 parts by weight. After the dispersion, it was granulated by a stirring granulation method. This granulated product is granulated to give granules, and then 70 parts by weight of light anhydrous silicic acid and 40 parts by weight of magnesium stearate are added to the granules, using a V-type mixer (manufactured by Tokuju Kogakusho Co., Ltd.). Mix for 15 minutes. This mixture was tableted with a tableting pressure of 9.8 kN / 杵 using a rotary tableting machine (collect 19, manufactured by Kikusui Seisakusho Co., Ltd.) to obtain circular tablets (diameter 10 mm, one tablet 360 mg).

  The tablets were examined for hardness and friability in the same manner as described in Example 1. The results showed that the hardness of this test tablet was 31.4N and the friability was only 0.12%.

Examples 3 to 5 and Comparative Example 1:
Test tablets having the formulations shown in Table 1 below were prepared.

  Specifically, each compounding component is mixed in advance at each weight ratio shown in Table 1, and an appropriate amount of ethanol is added thereto and kneaded to obtain a medium chain fatty acid triglyceride ((caprylic acid / capric acid) triglyceride, freezing point: about After being dispersed at −5 ° C.), it was granulated by an extrusion granulation method. This granulated product is sized and granulated, and then light anhydrous silicic acid (latter powder) and magnesium stearate are added to the granule, and it is mixed for 15 minutes with a V-type mixer (manufactured by Tokuju Kogakusho). Mixed. This mixture was tableted with a rotary tableting machine (collect 19, Kikusui Seisakusho Co., Ltd.) at a tableting pressure of 5, 10, 15, or 20 kN / kg, and a circular tablet (diameter 10 mm, one tablet 360 mg) Respectively.

  The hardness of each tablet was examined in the same manner as described in Example 1. The result is shown in FIG.

  As shown in FIG. 1, the tablet of the present invention was able to control the hardness in the range of 5 to 30 N in a wide range of tableting pressures of 5 to 20 kN / 杵.

  On the other hand, in the case of the tablet of Comparative Example 1 that does not contain medium chain fatty acid triglyceride, it is necessary to set the tableting pressure to about 5 to about 13.1 kN / 杵 to make the tablet hardness 5 to 50 N. In order to make the hardness 5-30 N, it was necessary to control the tableting pressure more strictly to about 5 to about 9.3 kN / 杵.

Furthermore, using the tablets of Examples 3 to 5 and Comparative Example 1 having a hardness of 20 N, a friability test of the tablets was performed. The friability test was performed according to the method described in Example 1. The results are shown in Table 2 below.

  As is apparent from Table 2, the compression-molded tablets of Examples 3 to 5 containing 3 to 7% by weight of medium chain fatty acid triglyceride (MCT) ((caprylic acid / capric acid) triglyceride, freezing point: about −5 ° C.) It has been demonstrated that it has very low friability and has sufficient strength for handling. On the other hand, in the case of the tablet of Comparative Example 1 not containing medium chain fatty acid triglycerides, the friability was very high.

Examples 6-9:
Test tablets having the formulations shown in Table 3 below were prepared.

  Specifically, each compounding component is mixed in advance at each weight ratio shown in Table 3, and an appropriate amount of ethanol is added thereto and kneaded to obtain a medium chain fatty acid triglyceride ((caprylic acid / capric acid) triglyceride, freezing point: about After being dispersed at −5 ° C.), it was granulated by an extrusion granulation method. The granulated product was granulated to give granules, and then magnesium stearate was added to the granules and mixed for 15 minutes with a V-type mixer (manufactured by Tokuju Kogakusho Co., Ltd.). This mixture was tableted with a rotary tableting machine (collect 19, manufactured by Kikusui Seisakusho Co., Ltd.) at a tableting pressure of 15 kN / 杵 to obtain circular tablets (diameter 10 mm, one tablet 365 mg).

  The tablets were examined for hardness and friability in the same manner as described in Example 1. The results are shown in the lower column of Table 3 above. As a result, all of the compression-molded tablets of Examples 6 to 9 containing 5% by weight of medium-chain fatty acid triglycerides ((caprylic acid / capric acid) triglyceride, freezing point: about −5 ° C.) have very low hardness. Nevertheless, it has been demonstrated that the degree of friability is low and it has sufficient strength for handling. Surprisingly, when a sugar alcohol such as D-mannitol, xylitol, or lactitol is added, it has an extremely low tablet hardness that cannot normally be assumed from the viewpoint of handling strength. It was revealed that the friability was low and it had sufficient strength for handling.

Example 10:
The test tablet of this example was prepared by the following method.
First, 62.5 parts by weight of pyridoxine hydrochloride, 42 parts by weight of hydroxypropyl cellulose, 270 parts by weight of corn starch, and 933.86 parts by weight of D-mannitol were mixed in advance, and an appropriate amount of ethanol was added thereto to combine them. After being dispersed with 43.2 parts by weight of triglyceride ((caprylic acid / capric acid) triglyceride, freezing point: about −5 ° C.) and 12 parts by weight of polysorbate 80, the mixture was granulated by an extrusion granulation method. The granulated product is sized to granules, and then 1.44 parts by weight of a fragrance, 50 parts by weight of light anhydrous silicic acid and 25 parts by weight of magnesium stearate are added to the granules, and a V-type mixer (( Mixed for 15 minutes. This mixture was tableted with a rotary tableting machine (Collect 19, Kikusui Seisakusho Co., Ltd.) at a tableting pressure of 15 kN / 杵 to obtain circular chewable tablets (diameter 10 mm, one tablet 360 mg).

The tablets were examined for hardness and friability in the same manner as described in Example 1.
As a result, the hardness of this test tablet was 23.5 N, the friability was 0.00%, and no cracks were observed.

  Furthermore, according to the disintegration test method (general test method Japanese Pharmacopoeia 15th revision), the disintegration property of this test tablet was tested. Specifically, the test tablet and the test liquid (using water) are put in a glass tester (n = 6), and the temperature of the test liquid is maintained at 37 ° C. ± 2 ° C., and 29 to 32 reciprocations per minute. Smoothly moved up and down with an amplitude of 53 to 57 mm. The time until no tablet residue was found in the tester was measured. As a result, the disintegration time of this test tablet is as short as 1.8 to 3.2 minutes, and when a nonionic surfactant (polysorbate 80) is added, a nonionic surfactant is not added ( It was also revealed that the disintegration time is extremely short compared to Example 3 and the like.

  As mentioned above, this invention was illustrated using preferable embodiment of this invention. However, it is understood that the scope of the present invention should be interpreted only by the description of the appended claims. Patents, patent applications, and references cited herein should be incorporated by reference as if the contents were specifically set forth herein. Is understood.

FIG. 1 is a graph showing the relationship between tableting pressure and hardness in compression molded tablets of Examples 3 to 5 and Comparative Example 1.

Claims (6)

  A compression-molded tablet containing 3 to 10% by weight of a medium-chain fatty acid triglyceride having a freezing point of -30 ° C to 15 ° C based on the whole tablet, and having a hardness of 5 to 50N.   The compression-molded tablet according to claim 1, further comprising a sugar alcohol.   The compression-molded tablet according to claim 2, wherein the sugar alcohol has a critical relative humidity at 37 ° C of 70% or more.   The compression-molded tablet according to claim 2 or 3, wherein the sugar alcohol is at least one selected from the group consisting of D-mannitol, xylitol, erythritol, maltitol, lactitol, and reduced palatinose.   The compression molding tablet in any one of Claims 1-4 whose friability of the said compression molding tablet is 1% or less.   The compression-molded tablet according to any one of claims 1 to 5, which is a chewable tablet.

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