JP5168712B2 - Nateglinide-containing preparation - Google Patents

Nateglinide-containing preparation Download PDF

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JP5168712B2
JP5168712B2 JP2006511837A JP2006511837A JP5168712B2 JP 5168712 B2 JP5168712 B2 JP 5168712B2 JP 2006511837 A JP2006511837 A JP 2006511837A JP 2006511837 A JP2006511837 A JP 2006511837A JP 5168712 B2 JP5168712 B2 JP 5168712B2
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nateglinide
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邦和 鈴木
渉 涌井
昭 矢吹
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

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Description

本発明は、糖尿病薬として有用なナテグリニドの製剤、さらに詳しくはナテグリニドの口腔内崩壊錠に関する。
ナテグリニド〔化合物名：Ｎ−（トランス−４−イソプロピルシクロヘキシルカルボニル）−Ｄ−フェニルアラニン〕は経口投与により優れた血糖降下作用を示し、糖尿病治療薬として有用であることが知られている（特許文献１）。
ナテグリニド原薬は非常に強い苦味を有するため、経口剤として用いる場合、錠剤の表面をコートするなどして苦味をマスキングさせる必要があった。一方、医薬品を患者の視点で考えた場合、摂取の容易性が求められている。ナテグリニドは、食後の高血糖を改善するという優れた薬ではあるが、その為に食前の投与が必要であった。しかしながら、これまでの製剤では投与時、薬剤と同時に水の摂取が必要であり、摂取時に水を必要としない製剤が求められていた。
一方、近年経口用の製剤において、服用時に水を必要としない経口用製剤が開発されている。これらの中で、口腔内で薬剤が崩壊しその後消化管において吸収される口腔内（速）崩壊錠と呼ばれる製剤が知られている。
ところで、ナテグリニド原薬は上記の様に非常に強い苦味を有するため、通常の手法で口腔内崩壊錠を製造した場合、服用時に口腔内で苦味を有する為、服用者に不快感を与え実用上問題であった。これまでナテグリニドを含有する製剤に関する発明が知られているが苦味を低減させた口腔内崩壊錠に関するものは知られていなかった。（特許文献２〜６）The present invention relates to a preparation of nateglinide useful as a diabetic drug, and more particularly to an orally disintegrating tablet of nateglinide.
Nateglinide [compound name: N- (trans-4-isopropylcyclohexylcarbonyl) -D-phenylalanine] exhibits an excellent hypoglycemic effect by oral administration and is known to be useful as a therapeutic drug for diabetes (Patent Document 1). ).
Since nateglinide drug substance has a very strong bitter taste, when used as an oral preparation, it was necessary to mask the bitter taste by coating the surface of the tablet. On the other hand, ease of ingestion is required when considering pharmaceuticals from the viewpoint of patients. Nateglinide is an excellent drug that improves postprandial hyperglycemia, but for that purpose it must be administered before meals. However, conventional preparations require water intake at the same time as the drug at the time of administration, and preparations that do not require water at the time of intake have been demanded.
On the other hand, in recent years, oral preparations that do not require water at the time of taking are being developed as oral preparations. Among these, a preparation called an intraoral (fast) disintegrating tablet is known in which a drug disintegrates in the oral cavity and is then absorbed in the digestive tract.
By the way, since nateglinide drug substance has a very strong bitter taste as described above, when an orally disintegrating tablet is produced by a normal method, it has a bitter taste in the oral cavity at the time of taking, giving the user unpleasantness and practical use. It was a problem. So far, inventions relating to preparations containing nateglinide are known, but those relating to orally disintegrating tablets with reduced bitterness have not been known. (Patent Documents 2 to 6)

特公平４−１５２２１号公報Japanese Patent Publication No. 4-15221 ＷＯ９８／２２１０５WO98 / 22105 ＷＯ０１／２１１５９WO01 / 21159 ＷＯ０１／４７５５７WO01 / 47557 ＷＯ０２／３４２５４WO02 / 34254 ＷＯ０２／４００１０WO02 / 40010

本発明の目的は、ナテグリニドを有効成分として含有する医薬組成物において、苦味を感じさせない製剤を提供する事である。
上記課題を解決するために鋭意検討した結果、ナテグリニド及び、有機酸または無機酸、甘味料、並びに香料の少なくともいずれか一つを含有する事により、口腔内で崩壊しても苦味が低減した製剤を提供する事が可能である事を見出し、本発明を完成させるに至った。
すなわち、本発明はナテグリニドを有効成分とする医薬組成物において、さらに有機酸または無機酸、甘味料及び香料からなる群から選ばれる少なくとも一つを含有する事を特徴とする組成物である。この場合、有機酸がアスコルビン酸、クエン酸、無水クエン酸、コハク酸、酒石酸、フマル酸及びリンゴ酸からなる群から選ばれ、無機酸がリン酸水素ナトリウム又はリン酸水素カルシウムであり、甘味料がサッカリンナトリウム又はアスパルテームであり、香料がＬ−メントール又はペパーミントであることが望ましく、さらには有機酸がクエン酸であり、無機酸がリン酸水素ナトリウムであり、甘味料がサッカリンナトリウムであり、香料がＬ−メントールであることが好ましい。
また、本発明はナテグリニドを有効成分とする医薬組成物において、さらに有機酸または無機酸、甘味料、及び香料を含有する組成物である。この場合、有機酸がアスコルビン酸、クエン酸、無水クエン酸、コハク酸、酒石酸、フマル酸又はリンゴ酸であり、無機酸がリン酸水素ナトリウム又はリン酸水素カルシウムであり、甘味料がサッカリンナトリウム又はアスパルテームであり、香料がＬ−メントール又はペパーミントであることが望ましく、さらには有機酸または無機酸が有機酸のクエン酸であるか無機酸のリン酸水素ナトリウムであり、甘味料がサッカリンナトリウムであり、香料がＬ−メントールであると好ましい。
また、上記の組成物は、口腔内崩壊錠、もしくは苦味が低減している口腔内崩壊錠である医薬組成物であるのが好ましい。
本発明により、糖尿病薬であるナテグリニドを含有する製剤において、口腔内で崩壊させても苦味を感じさせない製剤の提供が可能となった。An object of the present invention is to provide a pharmaceutical composition containing nateglinide as an active ingredient so as not to give a bitter taste.
As a result of intensive studies to solve the above-mentioned problems, a preparation that has reduced bitterness even when disintegrated in the oral cavity by containing nateglinide and at least one of organic or inorganic acids, sweeteners, and fragrances As a result, the present invention has been completed.
That is, the present invention is a pharmaceutical composition containing nateglinide as an active ingredient, and further contains at least one selected from the group consisting of organic acids or inorganic acids, sweeteners and fragrances. In this case, the organic acid is selected from the group consisting of ascorbic acid, citric acid, anhydrous citric acid, succinic acid, tartaric acid, fumaric acid and malic acid, the inorganic acid is sodium hydrogen phosphate or calcium hydrogen phosphate, and a sweetener Is saccharin sodium or aspartame, the flavor is preferably L-menthol or peppermint, the organic acid is citric acid, the inorganic acid is sodium hydrogen phosphate, the sweetener is sodium saccharin, and the flavor is L -Preferably menthol.
In addition, the present invention is a pharmaceutical composition containing nateglinide as an active ingredient, further containing an organic acid or inorganic acid, a sweetener, and a fragrance. In this case, the organic acid is ascorbic acid, citric acid, anhydrous citric acid, succinic acid, tartaric acid, fumaric acid or malic acid, the inorganic acid is sodium hydrogen phosphate or calcium hydrogen phosphate, and the sweetener is saccharin sodium or aspartame. It is desirable that the flavor is L-menthol or peppermint, the organic acid or inorganic acid is citric acid of organic acid or sodium hydrogen phosphate of inorganic acid, and the sweetener is sodium saccharin, Is preferably L-menthol.
Moreover, it is preferable that said composition is a pharmaceutical composition which is an orally disintegrating tablet or an orally disintegrating tablet with reduced bitterness.
According to the present invention, it is possible to provide a preparation containing nateglinide, which is a diabetic drug, without causing a bitter taste even when disintegrated in the oral cavity.

本発明の医薬組成物に含まれるナテグリニドは、特公平４−１５２２１号公報に記載の方法等にしたがって合成することができる。その用いる結晶形は特に限定されないが、特許第２５０８９４９号公報に記載のＨ型、もしくはＢ型が好ましく、特にＨ型が安定性の観点で特に好ましい。
本発明の医薬組成物に含まれる有機酸とは、有機化合物で酸の性質を持つものを言い、これらは塩の形態、例えばナトリウム及びカリウム等のアルカリ金属、カルシウム及びマグネシウム等のアルカリ土類金属、又はトリエタノールアミン等のアミン類との塩の形態でも構わない。具体的には、アスコルビン酸、クエン酸、無水クエン酸、コハク酸、酒石酸、フマル酸、リンゴ酸及びこれらのナトリウム塩及びカリウム塩等が挙げられる。酸の形態であるのが好ましく、アスコルビン酸、クエン酸、無水クエン酸、酒石酸及びリンゴ酸がより好ましく、特にクエン酸が苦味低減の観点で特に好ましい。
本発明の医薬組成物に含まれる無機酸とは、炭素原子を含まない酸を言い、これらは塩の形態、例えばナトリウム及びカリウム等のアルカリ金属、カルシウム及びマグネシウム等のアルカリ土類金属、又はトリエタノールアミン等のアミン類との塩の形態でも構わない。具体的には、リン酸、炭酸、リン酸水素ナトリウム、リン酸水素カルシウム、炭酸カルシウム等が挙げられる。塩の形態であるのが好ましく、リン酸水素ナトリウム及びリン酸水素カルシウムがより好ましく、特にリン酸水素ナトリウムが苦味低減の観点で特に好ましい。
本発明の医薬組成物に含まれる甘味料とは、医薬品または食品に甘味をつけさせるために用いる添加物または調味料を言い、具体的には糖類、糖アルコール類、サッカリン、サッカリンナトリウム、アスパルテーム等が挙げられ、サッカリンナトリウム及びアスパルテームが好ましく、特にサッカリンナトリウムが苦味低減の観点で特に好ましい。
本発明の医薬組成物に含まれる香料とは、医薬品、食品または化粧品などに芳香をそえるために加える物質を言い、具体的にはＬ−メントール、ペパーミントパウダー、メロン、柑橘類、ベリー類、パイナップル、バニラ、コーヒー、コーラ、サイダー、ヨーグルト、ミルク、シナモンが挙げられ、Ｌ−メントール及びペパーミントパウダーが好ましく、特にＬ−メントールが苦味低減の観点で特に好ましい。
特に、クエン酸とサッカリンナトリウムとＬ−メントールとを含有するのが好ましい。Nateglinide contained in the pharmaceutical composition of the present invention can be synthesized according to the method described in Japanese Patent Publication No. 4-15221. The crystal form used is not particularly limited, but the H type or B type described in Japanese Patent No. 2508949 is preferable, and the H type is particularly preferable from the viewpoint of stability.
The organic acid contained in the pharmaceutical composition of the present invention refers to an organic compound having acid properties, such as salt forms, for example, alkali metals such as sodium and potassium, and alkaline earth metals such as calcium and magnesium. Alternatively, it may be in the form of a salt with an amine such as triethanolamine. Specific examples include ascorbic acid, citric acid, anhydrous citric acid, succinic acid, tartaric acid, fumaric acid, malic acid, and sodium and potassium salts thereof. The acid form is preferred, ascorbic acid, citric acid, anhydrous citric acid, tartaric acid and malic acid are more preferred, and citric acid is particularly preferred from the viewpoint of reducing bitterness.
The inorganic acid contained in the pharmaceutical composition of the present invention means an acid containing no carbon atom, and these are in the form of a salt, for example, an alkali metal such as sodium and potassium, an alkaline earth metal such as calcium and magnesium, or It may be in the form of a salt with an amine such as ethanolamine. Specific examples include phosphoric acid, carbonic acid, sodium hydrogen phosphate, calcium hydrogen phosphate, calcium carbonate, and the like. The salt form is preferred, sodium hydrogen phosphate and calcium hydrogen phosphate are more preferred, and sodium hydrogen phosphate is particularly preferred from the viewpoint of reducing bitterness.
The sweetener contained in the pharmaceutical composition of the present invention refers to an additive or seasoning used for sweetening a pharmaceutical product or food, and specifically includes sugars, sugar alcohols, saccharin, saccharin sodium, aspartame and the like. Saccharin sodium and aspartame are preferable, and saccharin sodium is particularly preferable from the viewpoint of reducing bitterness.
The fragrance contained in the pharmaceutical composition of the present invention refers to a substance to be added in order to add fragrance to pharmaceuticals, foods or cosmetics, specifically L-menthol, peppermint powder, melon, citrus fruits, berries, pineapple, Examples include vanilla, coffee, cola, cider, yogurt, milk, and cinnamon. L-menthol and peppermint powder are preferable, and L-menthol is particularly preferable from the viewpoint of reducing bitterness.
In particular, it is preferable to contain citric acid, saccharin sodium and L-menthol.

本発明の医薬組成物の剤形としては、例えば、散剤、顆粒剤、細粒剤、錠剤、などが挙げられるが、好ましいものとして顆粒剤、細粒剤、錠剤が挙げられる。本発明の医薬組成物は錠剤の形態であるのが好ましく、一錠当たりのナテグリニドの含有量が30ｍｇ以上であるのが好ましい。
本発明の医薬組成物の製剤化には、その他の配合成分として、通常の経口製剤に用いられる添加剤を使用することができ、特に限定されないが、賦形剤、崩壊剤、結合剤、滑沢剤、着色剤等を適宜配合することができる。本発明の医薬組成物が口腔内崩壊錠の形態である場合、口腔内で錠剤を速やかに崩壊させるために、崩壊剤をさらに添加することが好ましい。崩壊剤としては、カルボキシメチルスターチナトリウム、カルメロース、カルメロースナトリウム、カルメロースカルシウム、クロスカルメロースナトリウム、クロスポビドン、低置換度ヒドロキシプロピルセルロース（乾燥品を定量するとき、ヒドロキシプロピル基を５．０〜１６．０％含む。日本薬局方第１３改正Ｄ−８８５〜Ｄ−８８８参照）、部分アルファー化デンプン等が挙げられ、特にカルメロース、カルボキシメチルスターチナトリウム、クロスポビドンが好ましい。
崩壊剤の添加量は、ナテグリニドに対して、好ましくは1重量％〜10000重量％であり、より好ましくは5重量％〜1000重％部であり、さらに好ましくは10重量％〜400重量％である。
本発明の医薬組成物を製造する際のナテグリニドに対する他の添加剤の量は本発明の目的を達成できれば特に限定されないが、例えばナテグリニドに対して、それぞれの添加量は、有機酸で0.01〜2000重量%、無機酸で0.01〜4500重量%、甘味料で0.01〜45000重量%、香料で0.001〜200重量%で、好ましくは有機酸で0.1〜500重量%、無機酸で0.1〜500重量%、甘味料で0.1〜500重量%、香料で0.01〜50重量%である。さらに好ましくは有機酸で１〜200重量%、無機酸で1〜200重量%、甘味料で1〜100重量%、香料で1〜15重量%である。これらの添加物の添加量の総量は、0.001〜50000重量%で、好ましくは0.01〜5000重量%で、さらに好ましくは、0.1〜1000重量%で、より好ましくは１〜500重量%である。
特に、ナテグリニドに対して、クエン酸を100〜200重量％、サッカリンナトリウムを050〜200重量％、Ｌ−メントールを5〜15重量％含有する医薬組成物が好ましい。
上記、組成物を製造する事により、苦味の低減したナテグリニド含有の医薬組成物を提供する事ができる。本発明の医薬組成物は、現行ナテグリニド錠剤とのｖｉｔｒｏ評価における生物学同等性を確保することが可能となる。Examples of the dosage form of the pharmaceutical composition of the present invention include powders, granules, fine granules, tablets and the like, and preferred are granules, fine granules and tablets. The pharmaceutical composition of the present invention is preferably in the form of a tablet, and the content of nateglinide per tablet is preferably 30 mg or more.
In the formulation of the pharmaceutical composition of the present invention, additives used in normal oral preparations can be used as other ingredients, and are not particularly limited, but include excipients, disintegrants, binders, lubricants. A blending agent, a coloring agent and the like can be appropriately blended. When the pharmaceutical composition of the present invention is in the form of an orally disintegrating tablet, it is preferable to further add a disintegrating agent in order to rapidly disintegrate the tablet in the oral cavity. Disintegrants include sodium carboxymethyl starch, carmellose, carmellose sodium, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose (when the dry product is quantified, the hydroxypropyl group is added in an amount of 5.0 to 16.0% included (see Japanese Pharmacopoeia 13th revision D-885 to D-888), partially pregelatinized starch, and the like. Carmellose, sodium carboxymethyl starch, and crospovidone are particularly preferable.
The addition amount of the disintegrant is preferably 1% by weight to 10000% by weight, more preferably 5% by weight to 1000% by weight, and further preferably 10% by weight to 400% by weight with respect to nateglinide. .
The amount of the other additive with respect to nateglinide in producing the pharmaceutical composition of the present invention is not particularly limited as long as the object of the present invention can be achieved. For example, with respect to nateglinide, each additive amount is 0.01 to 2000 as an organic acid. % By weight, 0.01 to 4500% by weight for inorganic acid, 0.01 to 45000% by weight for sweetener, 0.001 to 200% by weight for flavor, preferably 0.1 to 500% by weight for organic acid, 0.1 to 500% by weight for inorganic acid, The sweetener is 0.1 to 500% by weight, and the flavor is 0.01 to 50% by weight. More preferably, the organic acid is 1 to 200% by weight, the inorganic acid is 1 to 200% by weight, the sweetener is 1 to 100% by weight, and the flavor is 1 to 15% by weight. The total amount of these additives is 0.001 to 50000% by weight, preferably 0.01 to 5000% by weight, more preferably 0.1 to 1000% by weight, and more preferably 1 to 500% by weight.
In particular, a pharmaceutical composition containing 100 to 200% by weight of citric acid, 050 to 200% by weight of saccharin sodium, and 5 to 15% by weight of L-menthol with respect to nateglinide is preferable.
By producing the above composition, a pharmaceutical composition containing nateglinide with reduced bitterness can be provided. The pharmaceutical composition of the present invention can ensure bioequivalence in vitro evaluation with current nateglinide tablets.

本発明の医薬組成物の製造方法としては、薬物と添加物との単純な混合したものを打錠することで製造可能であり、打錠前の粉体は乾式造粒法、湿式造粒法、流動層造粒法を用いることができる。
一方、上記組成物を用いて苦味の低減した口腔内崩壊錠を製造するには、通常の手法を用いる事により製造する事ができるが、例えば組成物の混合物または造粒物を低圧で、例えば５０Ｎ／ｍ2以下で打錠する方法等を用いる事ができる。具体的には、組成物を適当な混合機で混合した後、低圧打錠して製造する事もできるし、乾式造粒法(圧偏造粒法等)または湿式造粒法（流動層造粒法、攪拌造粒法等）など通常の造粒方法により造粒物を調製し低圧打錠して製造することができる。
これらの方法で製造する口腔内崩壊錠は、これまでの製剤と比べ水を必要としないで摂取でき、かつ口腔内で崩壊しても苦味が低減する製剤となる。該口腔内崩壊錠は、その硬度は５０Ｎ／ｍ2以下であるのが好ましく、さらに２０〜３０Ｎ／ｍ2であるのが好ましい。口腔内で、唾液により速やかに崩壊し、そのまま唾液とともに嚥下可能な製剤である。本発明の製剤は６０秒以内に崩壊し得る。As a method for producing the pharmaceutical composition of the present invention, it can be produced by tableting a simple mixture of a drug and an additive, and the powder before tableting may be dry granulation, wet granulation, Fluidized bed granulation can be used.
On the other hand, in order to produce an orally disintegrating tablet with reduced bitterness using the above composition, it can be produced by using a normal method. For example, a mixture or granulated product of the composition at a low pressure, for example, A method of tableting at 50 N / m 2 or less can be used. Specifically, after mixing the composition with a suitable mixer, it can be produced by tableting at low pressure, or by dry granulation (such as pressure-biased granulation) or wet granulation (fluidized bed granulation). The granulated product can be prepared by ordinary granulation methods such as a granulation method, a stirring granulation method, etc.), and can be manufactured by low-pressure tableting.
Orally disintegrating tablets produced by these methods can be ingested without the need for water as compared to conventional preparations, and become a preparation that reduces bitterness even when disintegrated in the oral cavity. The orally disintegrating tablets, hardness is preferably at most 50 N / m 2, still more preferably from 20-30 N / m 2. It is a preparation that can be rapidly disintegrated by saliva in the oral cavity and swallowed as it is. The formulations of the present invention can disintegrate within 60 seconds.

次に、実施例、比較例により本発明を更に詳細に述べる。
（実施例１〜２１）
表1に記載の化合物並びに重量の配合比をミルサー（岩谷産業、ミルサーＩＭＦ７００Ｇ）に添加し、２分間混合して混合粉体を得た。
（比較例１〜２）
表1に記載の化合物並びに重量の配合比をミルサー（岩谷産業、ミルサーＩＭＦ７００Ｇ）に添加し、２分間混合して混合粉体を得た。






Next, the present invention will be described in more detail with reference to examples and comparative examples.
(Examples 1 to 21)
The compound and weight ratio shown in Table 1 were added to Milcer (Iwatani Corporation, Milcer IMF700G) and mixed for 2 minutes to obtain a mixed powder.
(Comparative Examples 1-2)
The compound and weight ratio shown in Table 1 were added to Milcer (Iwatani Corporation, Milcer IMF700G) and mixed for 2 minutes to obtain a mixed powder.






Figure 0005168712
Figure 0005168712

（実施例２２）
上記実施例１〜２１および比較例１〜２で得た混合粉体について官能評価による味評価を実施した。評価は5段階で行った。表２に評価基準を、表３に味評価結果を示す(Example 22)
Taste evaluation by sensory evaluation was implemented about the mixed powder obtained in the said Examples 1-21 and Comparative Examples 1-2. Evaluation was performed in five stages. Table 2 shows the evaluation criteria, and Table 3 shows the taste evaluation results.

Figure 0005168712
Figure 0005168712

Figure 0005168712
Figure 0005168712

表３から分かるように、有機酸、無機酸、甘味料および香料の少なくとも１つ添加することにより、苦味を低減することができた。
さらにこれらを組み合わせることにより、苦味低減だけでなく後味も改善することが認められた。As can be seen from Table 3, the bitterness could be reduced by adding at least one of an organic acid, an inorganic acid, a sweetener and a fragrance.
Furthermore, by combining these, it was recognized that not only the bitterness was reduced but also the aftertaste was improved.

（実施例２２〜２４）
表４の造粒部に記載の化合物並びに配合比（重量）で、精製水を適量添加して攪拌造粒機（ダルトン、パワーニーダーPK150）により造粒した後、流動層乾燥機（フロイント産業、ＦＬＯ−１型）で乾燥させた。篩目開き1mmで強制篩過した後、同じく表４における後添加部分に記載の化合物を袋混合し、打錠用顆粒を調製する。得られた打錠用顆粒を打錠機（畑鉄工所、HTAP38LII、φ7.5ｍｍ）により低圧（20〜30Ｎ／ｍ2）打錠することにより口腔内崩壊錠を得た。(Examples 22 to 24)
After adding an appropriate amount of purified water and granulating with a stirring granulator (Dalton, Power Kneader PK150) at the compound and blending ratio (weight) listed in the granulation part of Table 4, a fluidized bed dryer (Freund Sangyo, FLO-1 type). After forced sieving with a 1 mm sieve opening, the compounds described in the post-added portion in Table 4 are mixed in a bag to prepare tableting granules. The obtained granules for tableting were tableted under low pressure (20-30 N / m 2 ) with a tableting machine (Hatabe Works, HTAP38LII, φ7.5 mm) to obtain an orally disintegrating tablet.

Figure 0005168712
Figure 0005168712

上記実施例で得た口腔内崩壊錠について表２に記載した評価基準による味評価及び口腔内崩壊時間測定を実施した。味評価は5段階で行った。口腔内崩壊時間測定は、本錠剤を口腔内に入れた時の崩壊時間を測定した。評価結果を表５に示す。表５から分かるように、有機酸（または無機酸）、甘味料および香料を混合粉体と同じ配合比で添加し、かつ崩壊剤を添加した口腔内崩壊錠は、混合粉体と同様の苦味低減効果を有すると共に、口腔内崩壊時間も60秒以内と速い崩壊特性が認められた。   For the orally disintegrating tablets obtained in the above examples, taste evaluation and oral disintegration time measurement according to the evaluation criteria described in Table 2 were performed. Taste evaluation was performed in five stages. In the oral disintegration time measurement, the disintegration time when the tablet was placed in the oral cavity was measured. The evaluation results are shown in Table 5. As can be seen from Table 5, the orally disintegrating tablet to which the organic acid (or inorganic acid), sweetener and fragrance were added at the same blending ratio as the mixed powder and the disintegrant was added has the same bitter taste as the mixed powder. In addition to reducing effects, the disintegration time in the oral cavity was as fast as 60 seconds or less.

Figure 0005168712
Figure 0005168712

Claims (12)

ナテグリニドを有効成分とする医薬組成物において、さらに有機酸または無機酸と、甘味料と、香料とを含有し、
有機酸がアスコルビン酸、クエン酸、無水クエン酸、酒石酸、フマル酸、リンゴ酸及びこれらの塩からなる群から選ばれ、無機酸がリン酸水素ナトリウム、又はリン酸水素カルシウムのいずれかであり、甘味料がサッカリンナトリウムであり、香料がＬ−メントール、又はペパーミントのいずれかであり、
ナテグリニドに対し、有機酸または無機酸を1〜200重量％、甘味料を1〜500重量％、香料を1〜200重量％なる量で含む事を特徴とする前記医薬組成物。In a pharmaceutical composition containing nateglinide as an active ingredient, it further contains an organic acid or inorganic acid, a sweetener, and a fragrance,
The organic acid is selected from the group consisting of ascorbic acid, citric acid, anhydrous citric acid, tartaric acid, fumaric acid, malic acid and salts thereof, and the inorganic acid is either sodium hydrogen phosphate or calcium hydrogen phosphate, The sweetener is sodium saccharin and the flavor is either L-menthol or peppermint;
The said pharmaceutical composition characterized by including 1 to 200 weight% of organic acid or inorganic acid, 1 to 500 weight% of sweetener, and 1 to 200 weight% of fragrance | flavor with respect to nateglinide. ナテグリニドを有効成分とする医薬組成物において、さらにクエン酸、甘味料及び香料を含有し、
甘味料がサッカリンナトリウムであり、香料がＬ−メントールであり、
ナテグリニドに対し、クエン酸を1〜200重量％、甘味料を1〜500重量％、香料を1〜200重量％なる量で含む事を特徴とする前記医薬組成物。In the pharmaceutical composition containing nateglinide as an active ingredient, it further contains citric acid, sweetener and flavor ,
The sweetener is sodium saccharin, the flavor is L-menthol,
The pharmaceutical composition comprising nateglinide in an amount of 1 to 200% by weight of citric acid, 1 to 500% by weight of sweetener, and 1 to 200% by weight of flavor. ナテグリニドを有効成分とする医薬組成物において、さらにリン酸水素ナトリウム、甘味料及び香料を含有し、
甘味料がサッカリンナトリウムであり、香料がＬ−メントールであり、
ナテグリニドに対し、リン酸水素ナトリウムを1〜200重量％、甘味料を1〜500重量％、香料を1〜200重量％なる量で含む事を特徴とする前記医薬組成物。In the pharmaceutical composition containing nateglinide as an active ingredient, further containing sodium hydrogen phosphate, sweetener and flavor ,
The sweetener is sodium saccharin, the flavor is L-menthol,
The pharmaceutical composition comprising sodium hydrogenphosphate in an amount of 1 to 200% by weight, sweetener in an amount of 1 to 500% by weight, and a fragrance in an amount of 1 to 200% by weight with respect to nateglinide. 口腔内崩壊錠である請求項１〜３いずれか１項記載の医薬組成物。  The pharmaceutical composition according to any one of claims 1 to 3, which is an orally disintegrating tablet. さらに、崩壊剤を含有する請求項４記載の医薬組成物。  Furthermore, the pharmaceutical composition of Claim 4 containing a disintegrating agent. 崩壊剤が、カルボキシメチルスターチナトリウム、カルメロース、カルメロースナトリウム、カルメロースカルシウム、クロスカルメロースナトリウム、クロスポビドン及び低置換度ヒドロキシプロピルセルロースからなる群から選ばれる請求項５記載の医薬組成物。  The pharmaceutical composition according to claim 5, wherein the disintegrant is selected from the group consisting of sodium carboxymethyl starch, carmellose, carmellose sodium, carmellose calcium, croscarmellose sodium, crospovidone and low-substituted hydroxypropylcellulose. ナテグリニドに対し、200重量％のクエン酸又は無水クエン酸を含有する医薬組成物。  A pharmaceutical composition comprising 200% by weight of citric acid or anhydrous citric acid with respect to nateglinide. ナテグリニドに対し、200重量％クエン酸、100重量％のサッカリンナトリウム、5重量％のL-メントールと、900重量％のコーンスターチとを含有する医薬組成物。  A pharmaceutical composition containing 200% by weight citric acid, 100% by weight sodium saccharin, 5% by weight L-menthol, and 900% by weight corn starch relative to nateglinide. ナテグリニドに対し、200重量％のクエン酸、50重量％のサッカリンナトリウム、5重量％のL-メントールと、900重量％のエリスリトールとを含有する医薬組成物。  A pharmaceutical composition comprising 200% by weight citric acid, 50% by weight sodium saccharin, 5% by weight L-menthol and 900% by weight erythritol, relative to nateglinide. ナテグリニドに対し、200重量％のクエン酸、200重量％のサッカリンナトリウム、15重量％のL-メントールと、450重量％のコーンスターチとを含有する医薬組成物。  A pharmaceutical composition comprising 200% by weight citric acid, 200% by weight sodium saccharin, 15% by weight L-menthol and 450% by weight corn starch relative to nateglinide. ナテグリニドに対し、200重量％のクエン酸、100重量％のサッカリンナトリウム、10重量％のL-メントールと、100重量％のコーンスターチとを含有する医薬組成物。  A pharmaceutical composition comprising 200% by weight citric acid, 100% by weight sodium saccharin, 10% by weight L-menthol and 100% by weight corn starch relative to nateglinide. ナテグリニドに対し、100重量％のクエン酸、100重量％のサッカリンナトリウム、10重量％のL-メントールと、200重量％のエリスリトールとを含有する医薬組成物。  A pharmaceutical composition comprising 100% by weight citric acid, 100% by weight sodium saccharin, 10% by weight L-menthol and 200% by weight erythritol with respect to nateglinide.
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