JP3988149B2 - Pharmaceutical additives - Google Patents
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- JP3988149B2 JP3988149B2 JP2005344540A JP2005344540A JP3988149B2 JP 3988149 B2 JP3988149 B2 JP 3988149B2 JP 2005344540 A JP2005344540 A JP 2005344540A JP 2005344540 A JP2005344540 A JP 2005344540A JP 3988149 B2 JP3988149 B2 JP 3988149B2
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本発明は、食品、医薬品、飼料等の分野における製剤用添加剤に関し、さらに詳しくはトレハロースからなる製剤用添加剤に関する。 The present invention relates to a pharmaceutical additive in the fields of foods, pharmaceuticals, feeds, and the like, and more particularly to a pharmaceutical additive comprising trehalose.
食品、医薬品、飼料等の分野における錠剤、丸剤、顆粒剤、散剤（細粒剤をふくむ）、トローチ剤及び咀嚼剤等の固形製剤や注射剤、懸濁剤、乳剤、エリキシル剤、シロップ剤等の液状製剤の製造には、有効成分とその保存中の性状及び品質の基準を確保し、又はその有用性を高めるため、賦形剤、安定剤、保存剤、緩衝剤などの適当な添加剤が用いられている。添加剤は、前記製剤の投与量において無害でなければならないし、その製剤の治療効果を障害し、又は試験に支障をきたすものであってはならない。 Solid preparations and injections such as tablets, pills, granules, powders (including fine granules), troches, and chews in the fields of food, pharmaceuticals, feeds, suspensions, emulsions, elixirs, syrups In order to secure the active ingredient and its properties and quality standards during storage, or to increase its usefulness, suitable additions of excipients, stabilizers, preservatives, buffering agents, etc. The agent is used. The additive must be harmless in the dosage of the formulation and must not interfere with the therapeutic effect of the formulation or interfere with the study.
従来より、固形製剤には、馬鈴薯澱粉、とうもろこし澱粉等の澱粉類、乳糖、蔗糖、ブドウ糖、マンニトールなどの糖類、リン酸カルシウム、沈降炭酸カルシウムなどの無機塩類など各種の賦形剤が有効成分の希釈の目的で用いられている。また、難溶性薬物の溶解性を高めるための添加剤、例えば固溶体化法及び混合粉砕法で用いる担体として、各種の糖類及びセルロース誘導体並びにポリビニルピロリドン等の高分子物質が用いられている（後掲特許文献１等）。 Conventionally, various excipients such as starches such as potato starch and corn starch, saccharides such as lactose, sucrose, glucose and mannitol, inorganic salts such as calcium phosphate and precipitated calcium carbonate, etc. are diluted in the solid formulation. It is used for the purpose. In addition, various sugars, cellulose derivatives, and polymer substances such as polyvinylpyrrolidone are used as additives for enhancing the solubility of poorly soluble drugs, for example, carriers used in the solid solution method and the mixed pulverization method (described later). Patent Document 1).
他方、錠剤は従来より湿式打錠法（間接打錠法）によって製造されていたが、近年では、製造工程の簡略化、造粒工程の省略化を目的とした直接打錠法が広く利用されている。この直接打錠法は、有効成分と各種の添加剤よりなる混合末が良好な流動性や圧縮成形性を示す必要があり、さらに服用後の良好な崩壊性を得るため適切な直接打錠用賦形剤を用いることが必要である。この、直接打錠用賦形剤としては、古くから微結晶セルロース、リン酸水素カルシウム及びソルビトールが用いられてきた。前記打錠用賦形剤の他には、例えば、キシランとグルコマンナンよりなる打錠用賦形剤（後掲特許文献２）、セルロース粉末とヒドロキシプロピルスターチ粉末の分散液を噴霧乾燥した圧縮成型用賦形剤（後掲特許文献３）、及び水溶性グルカン（後掲特許文献４）等が開示されている。また、直接打錠用の賦形剤として、噴霧乾燥や流動層造粒した乳糖が市販されている（商品名「Fast Flow-Hydrous N. F. Spray Dryed」Foremost社製、商品名「ダイラクトーズ」フロイント産業社製、商品名「タブレトーズ」太陽化学社製）。 On the other hand, tablets have been conventionally produced by a wet tableting method (indirect tableting method), but in recent years, direct tableting methods have been widely used for the purpose of simplifying the production process and omitting the granulation process. ing. In this direct tableting method, the mixed powder consisting of the active ingredient and various additives needs to exhibit good fluidity and compression moldability, and for direct tableting suitable for obtaining good disintegration after taking It is necessary to use excipients. As the direct tableting excipient, microcrystalline cellulose, calcium hydrogen phosphate and sorbitol have been used for a long time. In addition to the tableting excipient, for example, a tableting excipient comprising xylan and glucomannan (Patent Document 2 below), a compression molding obtained by spray drying a dispersion of cellulose powder and hydroxypropyl starch powder Excipients for use (Patent Document 3) and water-soluble glucan (Patent Document 4) are disclosed. In addition, spray-dried and fluidized-bed granulated lactose is commercially available as an excipient for direct tableting (trade name “Fast Flow-Hydrous NF Spray Dryed” manufactured by Foremost, trade name “Dilactose” Freund Sangyo Co., Ltd. Product name "Tablets" manufactured by Taiyo Chemical Co., Ltd.).
トローチ剤、咀嚼剤あるいは舌下錠は有効成分と添加剤が共に水可溶性であることが望ましく、完全可溶性賦形剤の添加が必要で、従来より蔗糖、乳糖、マンニトール及びキシリトール等の糖類が用いられている（後掲特許文献５および６）。従って、水に不溶である澱粉類、無機塩類及び微結晶セルロースは前記製剤において賦形剤としての使用が制限される。 For lozenges, chewing agents or sublingual tablets, it is desirable that both active ingredients and additives are water-soluble, and it is necessary to add completely soluble excipients. Conventionally, sugars such as sucrose, lactose, mannitol and xylitol have been used. (Patent Documents 5 and 6 below). Therefore, starches, inorganic salts and microcrystalline cellulose that are insoluble in water are limited in use as excipients in the formulation.
注射剤には、溶解補助剤としての使用、あるいは凍結乾燥された製剤においては、再溶解する際の溶解性を高めるためデキストランを始めとする多糖類の添加剤が使用されている。 For injections, polysaccharide additives such as dextran are used for use as a solubilizing agent or in lyophilized preparations in order to increase the solubility when redissolved.
特殊な添加剤としては、例えば、癌細胞へ特異的に制癌作用物質を到達させるために、癌細胞に対して親和性を有する高分子物質に制癌作用物質を結合させた高分子プロドラッグが提案されており、デキストラン等の多糖類、アルブミン等の蛋白、ペプタイド類及びポリエチレングリコール等の合成高分子がその担体として用いられている（後掲非特許文献１等）。 As a special additive, for example, a polymer prodrug in which an anticancer drug is bound to a high molecular substance having affinity for cancer cells in order to reach the cancer cell specifically to cancer cells A polysaccharide such as dextran, a protein such as albumin, a peptide, and a synthetic polymer such as polyethylene glycol are used as the carrier (Non-Patent Document 1, etc. described later).
ところが、添加剤の多くは、有効成分と配合することにより、程度の差はあるにせよ、配合変化を起し有効成分の経時的な品質劣化を引き起こす。例えば、添加剤として繁用されている乳糖は、その還元性故に有効成分がそれに感受性の高い場合は使用できないし、第１級アミンをもつ有効成分とはメイラード反応を起して褐色の反応物を生成する。また、ビタミンＤ３誘導体は、乳糖と配合すると著しく分解することが知られている（後掲特許文献７）。リン酸水素カルシウムや繊維素グリコール酸カルシウムは、カルシウムと反応性のある有効成分には用いることができない。馬鈴薯澱粉やとうもろこし澱粉あるいは微結晶セルロース等の有効成分と反応性の少ない添加剤は、混合性や流動性は良いものの、圧縮成型性が悪い、あるいは流動性が悪い等の欠点を有している。さらに、馬鈴薯澱粉を始めとする前記添加剤は、水に不溶であり、トローチ剤や咀嚼剤に使用すると、舌ざわりが悪く好ましい服用感を得られない。 However, many of the additives are blended with the active ingredient to cause a change in the blend and cause deterioration of the quality of the active ingredient over time, although there is a difference in degree. For example, lactose frequently used as an additive cannot be used when the active ingredient is sensitive to it due to its reducibility, and it is a brown reactant resulting from a Maillard reaction with an active ingredient having a primary amine. Is generated. Further, it is known that vitamin D 3 derivatives are significantly degraded when blended with lactose (Patent Document 7 described later). Calcium hydrogen phosphate and calcium fibrin glycolate cannot be used as active ingredients reactive with calcium. Additives that are less reactive with active ingredients such as potato starch, corn starch, or microcrystalline cellulose have good blendability and fluidity, but have disadvantages such as poor compression moldability and poor fluidity. . Furthermore, the said additive including potato starch is insoluble in water, and when it is used for a troche or a chewing agent, the feeling of a tongue is bad and favorable taking feeling cannot be obtained.
このように、従来の添加剤には、有効成分の希釈をはじめとする前述の各種の目的に使用でき、且つ有効成分との反応性が低いものはなく、これらの要望を満たす添加剤の開発が望まれている。
本発明の課題は、食品、医薬品、飼料等の分野における有効成分の希釈をはじめとする各種の目的に使用でき、且つ有効成分との反応性が低い製剤用添加剤を提供することにある。 An object of the present invention is to provide a pharmaceutical additive that can be used for various purposes including dilution of an active ingredient in the fields of foods, pharmaceuticals, feeds and the like and has low reactivity with the active ingredient.
トレハロースは、水に可溶な柱状晶として得られ、融点２０３℃、加水分解で２モルのＤ−グルコースを与えること、非還元性であることが知られている。本発明者らは、トレハロースの前記諸性質の他に、その味、水溶液の粘度及び透明度、結晶の粉砕特性、さらにはその粉末の色調、流動性、圧縮成型性、濡れ特性、吸湿特性、有効成分との配合変化の有無を詳細に調べた。その結果、トレハロースがこれまで知られている添加剤には見られない、添加剤として有用な諸特性を併せもつことを見出し本発明を完成することができた。すなわち、本発明は、次の（ａ）〜（ｂ）のいずれかの製剤用賦形剤を使用し、流動層造粒法により作成されたことを特徴とする製剤：（ａ）無水α，α−トレハロースを除くトレハロースからなる流動層造粒用の製剤用賦形剤及び（ｂ）さらに微結晶セルロース、澱粉、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロースナトリウム、リン酸水素カルシウム、ポリビニルアルコールおよびポリビニルピロリドンからなる群から選ばれる一以上をも含有する（ａ）の流動層造粒用の製剤用賦形剤を提供するものである。 It is known that trehalose is obtained as columnar crystals soluble in water, has a melting point of 203 ° C., gives 2 mol of D-glucose by hydrolysis, and is non-reducing. In addition to the above-mentioned properties of trehalose, the inventors of the present invention have a taste, viscosity and transparency of an aqueous solution, crystal grinding properties, color tone, fluidity, compression moldability, wetting properties, moisture absorption properties, and effective properties of the powder. The presence or absence of a change in formulation with the ingredients was examined in detail. As a result, it has been found that trehalose has properties useful as an additive that have not been found in known additives, and the present invention has been completed. That is, the present invention is a formulation characterized in that it is prepared by a fluidized bed granulation method using any of the following formulation excipients (a) to (b): (a) anhydrous α, Formulation excipient for fluidized bed granulation consisting of trehalose excluding α-trehalose and (b) microcrystalline cellulose, starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, calcium hydrogen phosphate, polyvinyl alcohol and The formulation excipient for fluidized bed granulation (a), which also contains one or more selected from the group consisting of polyvinylpyrrolidone , is provided.
トレハロースには、α，α−トレハロース、α，β−トレハロース又はβ，β−トレハロースの３種が存在する。このうち、製剤用の添加剤としては、天然に存在するα，α−トレハロースが好ましい。トレハロースの水溶液は、無色透明で、粘性が低く、また、僅かな甘味を呈し服用しやすい特性をもつ。 There are three types of trehalose: α, α-trehalose, α, β-trehalose or β, β-trehalose. Of these, naturally-occurring α, α-trehalose is preferable as an additive for preparations. An aqueous solution of trehalose is colorless and transparent, has a low viscosity, has a slight sweetness and is easy to take.
２００メッシュ（７４μｍ）篩を全通する粉末状のトレハロースは、有効成分の希釈を目的とする賦形剤として優れた混合性を示し、製剤の含量均一性を確保できる。トレハロースは、機械粉砕等により容易に粒度のコントロールが行える。そこで、トレハロースを使用目的あるいは有効成分の特性に応じた粒度に加工することにより、その便宜性は更に向上する。 Powdered trehalose that passes through a 200 mesh (74 μm) sieve exhibits excellent mixing properties as an excipient for the purpose of diluting the active ingredient, and can ensure the uniformity of the content of the preparation. Trehalose can be easily controlled in particle size by mechanical grinding or the like. Therefore, convenience is further improved by processing trehalose into a particle size according to the purpose of use or the characteristics of the active ingredient.
トレハロースは澱粉類の添加剤とは異なり、優れた圧縮成型性を示す。更に、圧縮成型物の色調は、乳糖の成型物とは異なり白色度が高い。トレハロースは前記粒度をコントロールしたものの他、その他の添加剤例えばセルロース誘導体との混合物を造粒（転動造粒、流動層造粒等）あるいは噴霧乾燥することにより、打錠用の賦形剤、特に直接打錠用の添加剤として有用な添加剤となり得る。 Trehalose, unlike starch additives, exhibits excellent compression moldability. Further, the color tone of the compression molded product is high in whiteness unlike the molded product of lactose. Trehalose is a tableting excipient by granulating (rolling granulation, fluidized bed granulation, etc.) or spray-drying a mixture with other additives such as cellulose derivatives, in addition to those controlling the particle size, In particular, it can be an additive useful as an additive for direct tableting.
さらに、トレハロースは、水によく溶け僅かな甘味を有する服用感の優れた添加剤で、トローチ剤、舌下錠及び咀嚼錠における水可溶性賦形剤として使用できる。 Furthermore, trehalose is an additive with a good taste that dissolves well in water and has a slight sweetness, and can be used as a water-soluble excipient in lozenges, sublingual tablets and chewable tablets.
トレハロースは、その単味またはポリビニルアルコール、ポリビニルピロリドン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース等との併用により難溶性薬物の溶解性改善、例えば固溶体化法や混合粉砕法の添加剤としても有用である。 Trehalose is useful as an additive for improving the solubility of a poorly soluble drug, for example, a solid solution method or a mixed pulverization method by using it alone or in combination with polyvinyl alcohol, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and the like.
本発明の製剤用添加剤をシロップ剤の甘味賦形剤として使用すると、蔗糖を用いた場合に比べ甘味が抑えられた服用感のよい製剤が得られる。また、注射剤の有効成分の溶解補助剤及びデキストランに代わる凍結乾燥製剤用の添加剤としても有用である。 When the additive for preparation of the present invention is used as a sweetening excipient for syrup, a preparation having a good feeling of taking in which sweetness is suppressed as compared with the case of using sucrose can be obtained. In addition, it is also useful as a solubilizing agent for active ingredients of injections and as an additive for freeze-dried preparations in place of dextran.
トレハロースは、製剤学的に安定な二糖類であり、有効成分との反応性が低い。また、水によく溶け、僅かな甘味をもつ服用感に優れた糖類である。さらに、その粉末は混合性、造粒性及び圧縮成型性に優れ、且つ有効な流動性を示す。従って、トレハロースは、食品、医薬品、飼料等の分野における有効成分の希釈をはじめとする各種の目的に使用でき、且つ有効成分との反応性が少ない製剤用の添加剤となり得る。 Trehalose is a pharmaceutically stable disaccharide and has low reactivity with active ingredients. In addition, it is a saccharide that dissolves well in water and has a slight sweetness and is excellent in taking feeling. Furthermore, the powder is excellent in mixing property, granulation property and compression moldability, and exhibits effective fluidity. Therefore, trehalose can be used for various purposes such as dilution of active ingredients in the fields of foods, pharmaceuticals, feeds and the like, and can be an additive for preparations having low reactivity with active ingredients.
本発明を以下の実施例によって具体的に説明する。 The present invention is specifically illustrated by the following examples.
実施例１：トレハロースを賦形剤とした流動層造粒
１，６−ジヒドロ−２−｛２−（２−メチルプロポキシ）アニリノ｝−６−オキソ−５−ピリミジンカルボン酸（以下、化合物という）は、抗アレルギー及び抗潰瘍作用をもつ水に難溶な化合物である（特告平３−３６８３５号公報、特開昭６２−２６７２２９号公報）。本化合物を含む錠剤を製造する場合は、スティッキング、キャッピング及びラミネーティング等の打錠障害が生じやすい。また、本化合物は、はっ水性が強く湿式造粒による粒状化が困難なうえ、これを含む錠剤は、崩壊時間が長い。このような特性をもつ前記化合物の粉末１２０ｇに、ヒドロキシプロピルセルロースＳＬ（日本曹達社製）４８ｇ、２００メッシュ（７４μｍ）篩を全通するα，α−トレハロース１６８ｇ、及びとうもろこし澱粉（日本食品加工社製）９６ｇを流動造粒コーティング装置（「ＦＬ−１０型」フロイント産業社製）に仕込み、入口温度５５℃の空気中で流動させながら、溶媒（３０％エタノール溶液）を噴霧空気圧０．６ｋｇ／ｃｍ２、噴霧空気量１８０ＮＬ／分、噴霧液速１２．５ｍｌ／ｍｉｎ、の条件で１０６分間噴霧した。噴霧後、同様の流動条件で乾燥した後、２４メッシュ（７１０μｍ）篩で造粒物を篩過し平均粒子径１９５μｍの造粒物を得た。
Example 1: Fluidized bed granulation using trehalose as an excipient 1,6-dihydro-2- {2- (2-methylpropoxy) anilino} -6-oxo-5-pyrimidinecarboxylic acid (hereinafter referred to as compound) Is a water-insoluble compound having antiallergic and antiulcer actions (Japanese Patent Publication No. 3-36835, Japanese Patent Laid-Open No. 62-267229). When a tablet containing the present compound is produced, tableting troubles such as sticking, capping and laminating are likely to occur. In addition, the present compound has high water repellency and is difficult to granulate by wet granulation, and a tablet containing the compound has a long disintegration time. Hydroxypropylcellulose SL (manufactured by Nippon Soda Co., Ltd.) 48 g, 200 mesh (74 μm) sieve α, α-trehalose 168 g, and corn starch (Nippon Food Processing Co., Ltd.) 96 g) was charged into a fluidized granulation coating device (“FL-10” manufactured by Freund Sangyo Co., Ltd.) and fluidized in air at an inlet temperature of 55 ° C., and a solvent (30% ethanol solution) was sprayed at an air pressure of 0.6 kg / Spraying was performed for 106 minutes under the conditions of cm 2 , the amount of spray air 180 NL / min, and the spray liquid speed 12.5 ml / min. After spraying and drying under the same flow conditions, the granulated product was sieved with a 24 mesh (710 μm) sieve to obtain a granulated product having an average particle size of 195 μm.
比較製剤１
比較製剤として、実施例１のトレハロースを乳糖に代えた他は、実施例１と同様にして平均粒子径１８５μｍの造粒物を得た。
Comparative preparation 1
As a comparative preparation, a granulated product having an average particle size of 185 μm was obtained in the same manner as in Example 1 except that trehalose in Example 1 was replaced with lactose.
実施例２
２００メッシュ篩（７４μｍ）を全通するトレハロース４００ｇを流動造粒コーティング装置（「ＦＬ−１０型」フロイント産業社製）に仕込み、入口温度５５℃の空気中で流動させながら、溶媒（３０％エタノール溶液）を噴霧空気圧０．６ｋｇ／ｃｍ２、噴霧空気量１８０ＮＬ／分で１４５０ｍｌ噴霧して造粒物を得た。
Example 2
400 g of trehalose passing through a 200 mesh sieve (74 μm) was charged into a fluidized granulation coating apparatus (“FL-10” manufactured by Freund Sangyo Co., Ltd.) and fluidized in air at an inlet temperature of 55 ° C. 1450 ml of the solution was sprayed at a spraying air pressure of 0.6 kg / cm 2 and a spraying air amount of 180 NL / min to obtain a granulated product.
実施例３
実施例１の造粒物を篩にかけた造粒物１４４ｇ（自社製）に、崩壊剤として架橋カルボキシメチルセルロースナトリウム（商品名「アクジゾル」旭化成社製）８ｇ、及び実施例２の造粒物（自社製）８２ｇをＶ型混合機（品川製作所製）に入れ、１分間混合後、さらに滑沢剤としてタルク（富士タルク社製）３ｇとステアリン酸マグネシウム（太平化学）３ｇを入れて３０秒間混合した。前記混合末を打錠機「コレクト１２ＨＵＫ」（菊水製作所製）にて、直径７ｍｍの杵で、１２０ｍｇずつ打錠（予圧０．３ｔ／ｃｍ２、本圧０．８ｔ／ｃｍ２、ターンテーブル回転数４０ｒｐｍ）し化合物約２０ｍｇを含有する裸錠を得た。
Example 3
144 g of granulated product obtained by sieving the granulated product of Example 1 (made in-house), 8 g of sodium carboxymethylcellulose (trade name “Akizol” manufactured by Asahi Kasei Co., Ltd.) as a disintegrant, and granulated product of Example 2 (in-house) 82 g) was put in a V-type mixer (Shinagawa Seisakusho), mixed for 1 minute, and further 3 g of talc (made by Fuji Talc) and 3 g of magnesium stearate (Taihei Chemical) were mixed as a lubricant and mixed for 30 seconds. . The mixed powder at a tableting machine "Correct 12HUK" (manufactured by Kikusui Seisakusho Ltd.), at a punch having a diameter of 7 mm, each 120mg tabletted (preload 0.3 t / cm 2, the pressure of 0.8 t / cm 2, rotating the turntable (Several 40 rpm) to obtain a bare tablet containing about 20 mg of the compound.
比較製剤２
比較製剤として、実施例１の造粒物の代わりに比較製剤１の造粒物を、実施例２の造粒物の代わりに造粒乳糖（商品名「ダイラクトーズ」フロイント産業社製）を用いた他は、実施例３と同様にして、化合物約２０ｍｇを含有する裸錠を得た。
Comparative preparation 2
As a comparative preparation, the granulated product of Comparative preparation 1 was used in place of the granulated product of Example 1, and granulated lactose (trade name “Dilactose” manufactured by Freund Sangyo Co., Ltd.) was used instead of the granulated product of Example 2. Others were carried out similarly to Example 3, and obtained the naked tablet containing about 20 mg of compounds.
試験例１
実施例１及び比較製剤１の造粒物の粒度分布を篩分け法によりそれぞれ測定し、その結果を図１に示した。実施例１及び比較製剤１は、ほぼ同様の粒度分布を持ち、本発明の添加剤と乳糖は造粒性に差がないことが明らかとなった。従って、乳糖と配合変化する有効性成分の賦形剤として造粒性を低下させることなく製剤化できることが判った。
Test example 1
The particle size distribution of the granulated product of Example 1 and Comparative Formulation 1 was measured by a sieving method, and the results are shown in FIG. Example 1 and Comparative Formulation 1 have almost the same particle size distribution, and it was revealed that the additive of the present invention and lactose have no difference in granulation properties. Therefore, it has been found that it can be formulated as an excipient of an effective ingredient that is mixed with lactose without reducing granulation.
試験例２
実施例３及び比較製剤２の裸錠について、１錠ごとの化合物含有量をそれぞれ測定（高速液体クロマトグラム法）し、その結果を下記第１表に示した。本発明の製剤用添加剤を用いた裸錠に含量偏析は認められず、本発明の製剤用添加剤は、乳糖を用いた場合と同様の混合性（含量均一性）を得られることが判った。
Test example 2
About the naked tablet of Example 3 and Comparative preparation 2, the compound content for each tablet was measured (high performance liquid chromatogram method), and the results are shown in Table 1 below. Content segregation was not observed in the uncoated tablets using the formulation additive of the present invention, and it was found that the formulation additive of the present invention has the same mixing properties (content uniformity) as when lactose was used. It was.
試験例３
実施例３及び比較製剤２の裸錠について、それぞれ錠剤品質（錠剤重量、錠剤硬度及び崩壊時間）を測定し、その結果を下記第２表に示した。
Test example 3
The tablet quality (tablet weight, tablet hardness and disintegration time) was measured for each of the bare tablets of Example 3 and Comparative preparation 2, and the results are shown in Table 2 below.
本発明の製剤用添加剤は、造粒用の賦形剤としては粉末乳糖、打錠用の添加剤としては造粒乳糖（直接打錠用賦形剤）を用いた場合と同等の錠剤品質を得られることが判った。 The additive for formulation of the present invention has the same tablet quality as when powdered lactose is used as the excipient for granulation and granulated lactose (excipient for direct tableting) is used as the additive for tableting. It was found that
試験例４
実施例３で調製した裸錠、比較製剤２の裸錠及び化合物を微細化した粉末を被検薬として、溶出試験（ｐＨ５．６の緩衝液９００ｍｌ（３７℃）、パドル回転数１００ｒｐｍ）を行い、その結果を図２に示した。
Test example 4
A dissolution test (900 ml of pH 5.6 buffer solution (37 ° C., paddle rotation speed: 100 rpm)) was performed using the uncoated tablet prepared in Example 3, the uncoated tablet of Comparative Formulation 2, and the powder refined from the compound as the test drug. The results are shown in FIG.
図２から明らかなように、本発明の製剤用添加剤を使用した裸錠は、水可溶性の乳糖を用いた場合と同様の溶出性を示し、難溶性薬物の賦形剤として好ましい特性を持つことが判った。 As is apparent from FIG. 2, the uncoated tablet using the formulation additive of the present invention exhibits the same dissolution properties as when water-soluble lactose is used, and has preferable characteristics as an excipient for a poorly soluble drug. I found out.
試験例５
賦形剤と配合変化する有効成分として、特に糖類と反応するＬ−アルギニン１０ｇとα，α−トレハロース１０ｇに精製水を加えて１００ｍｌとした水溶液及び対照として前記水溶液のα，α−トレハロースの代わりに乳糖を用いた水溶液を調製し、この２種類の水溶液をそれぞれバイアルに分注して６０℃の恒温器中及び冷所（５℃）に２３時間保存した。前記の２種類の条件下で保存した後、それぞれの水溶液の外観を観察するとともに、精製水を対照として４３０ｎｍにおける透過率（％）を測定しその結果を下記第３表に示した。
Test Example 5
As an active ingredient mixed with excipients, in particular, 10 g of L-arginine that reacts with sugar and 10 g of α, α-trehalose was added purified water to make 100 ml, and instead of α, α-trehalose in the aqueous solution as a control An aqueous solution using lactose was prepared, and each of the two aqueous solutions was dispensed into vials and stored in a 60 ° C. incubator and in a cold place (5 ° C.) for 23 hours. After storing under the above two types of conditions, the appearance of each aqueous solution was observed, and the transmittance (%) at 430 nm was measured using purified water as a control. The results are shown in Table 3 below.
Ｌ−アルギニンと乳糖を含む水溶液は、加温虐待により褐色に変化し著しい透過率低下を示した。しかし、同様の条件で本発明の添加剤を用いた場合は、外観変化が認められず、また透過率の低下も僅かであった。このように本発明の製剤用添加剤は、添加剤との配合変化が懸念される有効成分に用いることができる。 The aqueous solution containing L-arginine and lactose turned brown due to heating abuse and showed a significant decrease in permeability. However, when the additive of the present invention was used under the same conditions, no change in appearance was observed and the transmittance was slightly reduced. Thus, the additive for formulation of this invention can be used for the active ingredient with which a mixing | blending change with an additive is anxious.
以上説明したように本発明の製剤用添加剤は、水によく溶け無色透明の僅かな甘味を有する粘性の少ない水溶液となり服用感に優れている。また、本発明の製剤用添加剤は、混合性、造粒性及び圧縮成型性に優れ良好な流動性を示す。更に、本発明の製剤用添加剤は製剤学的に安定で有効成分との反応性が少ない特性を持つ。上記の利点を兼ね備え、各種の添加剤の用途に使用できる本発明の製剤用添加剤は、産業に大いに貢献するものである。 As described above, the additive for preparation of the present invention dissolves well in water and becomes a colorless, transparent, slightly sweet aqueous solution with low viscosity, and is excellent in taking feeling. Moreover, the additive for formulation of this invention is excellent in mixing property, granulation property, and compression moldability, and shows favorable fluidity | liquidity. Furthermore, the pharmaceutical additive of the present invention has characteristics that are pharmaceutically stable and less reactive with active ingredients. The pharmaceutical additive of the present invention that has the above-mentioned advantages and can be used for various types of additives greatly contributes to the industry.
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