JP6012373B2 - Orally disintegrating tablets - Google Patents
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Description
本発明は口腔内崩壊錠に関する。 The present invention relates to an orally disintegrating tablet.
近年、疾病の治療において、患者のＱＯＬ（Ｑｕａｌｉｔｙ ｏｆ Ｌｉｆｅ）の改善を目的に、製剤学的工夫を凝らした製剤開発が盛んであり、口腔内崩壊錠は最も多く開発されている製剤である。口腔内崩壊錠は、口腔内の少量の唾液でも瞬時に崩壊することから、服用が容易であり、通常の錠剤では嚥下が困難な高齢者や小児に最適な製剤である。また水なしで服用できるため服用の場所や時間が制限されない利点も有する。
Ｌ−カルボシステインは、上気道炎や急性気管支炎の去痰薬として知られる薬剤であるが、１回投与量が５００ｍｇ（通常成人）と高用量であることから、ＱＯＬ改善の目的から口腔内崩壊錠の開発が望まれている。
Ｌ−カルボシステインを有効成分とする口腔内崩壊錠としては、遊離形として存在するＬ−カルボシステインにその医学的に許容しうる塩を配合した口腔内崩壊錠（特許文献１）、特定の平均粒子径を有するＬ−カルボシステインと非晶質状態のトレハロースを含有する造粒物を使用した口腔内崩壊錠（特許文献２）が知られている。
一方、イソマルトについては、イソマルトを賦形剤として高含量配合することで、高い崩壊性と錠剤硬度の口腔内崩壊錠が得られたとの報告がある（特許文献３）。
In recent years, in the treatment of diseases, for the purpose of improving QOL (Quality of Life) of patients, formulation development with pharmacological ingenuity has been actively performed, and orally disintegrating tablets are the most frequently developed formulations. Orally disintegrating tablets disintegrate instantaneously even with a small amount of saliva in the oral cavity, and thus are easy to take, and are the optimal preparation for elderly people and children who are difficult to swallow with ordinary tablets. Moreover, since it can be taken without water, it has the advantage that the place and time for taking are not limited.
L-carbocysteine is a drug known as an expectorant for upper respiratory tract inflammation and acute bronchitis. However, since the single dose is as high as 500 mg (usually adult), it disintegrates in the oral cavity for the purpose of improving QOL. Development of a lock is desired.
As an orally disintegrating tablet containing L-carbocysteine as an active ingredient, an orally disintegrating tablet containing L-carbocysteine present in a free form and a medically acceptable salt thereof (Patent Document 1), a specific average An orally disintegrating tablet (Patent Document 2) using a granulated product containing L-carbocysteine having a particle size and trehalose in an amorphous state is known.
On the other hand, regarding isomalt, there is a report that an orally disintegrating tablet having high disintegration property and tablet hardness was obtained by blending a high content of isomalt as an excipient (Patent Document 3).
Ｌ−カルボシステインを有効成分とする口腔内崩壊錠の製造方法は、いずれも圧縮成型した錠剤を加湿湿潤後、乾燥する工程を有するため、製造が複雑であった。また、賦形剤としてのイソマルトを多量に配合する口腔内崩壊錠では、錠剤が大型化してしまうためＱＯＬ上好ましくない。 The production methods for orally disintegrating tablets containing L-carbocysteine as an active ingredient are complicated in production because they all include a step of drying a compression-molded tablet after humidification and wetting. In addition, an orally disintegrating tablet containing a large amount of isomalt as an excipient is not preferable in terms of QOL because the tablet becomes large.
本発明の目的は、小型化されたＬ−カルボシステイン含有口腔内崩壊錠を一般的な生産設備にて生産性良く製造することにある。 An object of the present invention is to produce a miniaturized L-carbocysteine-containing orally disintegrating tablet with a general production facility with high productivity.
すなわち、本発明は、
（１）カルボシステイン、イソマルトおよび崩壊剤を含有し、カルボシステインの含有量が錠剤中７５質量％以上である口腔内崩壊錠、
（２）カルボシステインが、イソマルトとともに造粒された顆粒中に含まれる（１）に記載の口腔内崩壊錠、
（３）上記顆粒が、カルボシステインとイソマルトのみからなる顆粒である、（２）に記載の口腔内崩壊錠、
（４）上記顆粒が、流動層造粒法により製造されたものである（２）又は（３）に記載の口腔内崩壊錠、
（５）上記崩壊剤が、低置換ヒドロキシプロピルセルロース、クロスポビドン、カルボキシメチルスターチ塩およびカルメロース塩からなる群より選ばれる１種または２種以上である（１）〜（４）のいずれか１項に記載の口腔内崩壊錠、
（６）錠剤硬度が、５ｋｇ以上である（１）〜（５）のいずれか１項に記載の口腔内崩壊錠、
（７）さらに高甘味度甘味剤を含有する（１）〜（６）のいずれか１項に記載の口腔内崩壊錠、である。
That is, the present invention
(1) an orally disintegrating tablet containing carbocysteine, isomalt and a disintegrant, wherein the content of carbocysteine is 75% by mass or more in the tablet;
(2) The orally disintegrating tablet according to (1), wherein carbocysteine is contained in granules granulated with isomalt,
(3) The orally disintegrating tablet according to (2), wherein the granule is a granule composed only of carbocysteine and isomalt.
(4) The orally disintegrating tablet according to (2) or (3), wherein the granule is produced by a fluidized bed granulation method,
(5) Any one of (1) to (4), wherein the disintegrant is one or more selected from the group consisting of low-substituted hydroxypropylcellulose, crospovidone, carboxymethyl starch salt, and carmellose salt. Orally disintegrating tablets,
(6) The orally disintegrating tablet according to any one of (1) to (5), wherein the tablet hardness is 5 kg or more,
(7) The orally disintegrating tablet according to any one of (1) to (6), further comprising a high-intensity sweetener.
本発明により、優れた溶出性を有し、かつ、小型化されたＬ−カルボシステイン含有口腔内崩壊錠を、一般的な設備を用いて生産性良く製造することが可能となった。 According to the present invention, an L-carbocysteine-containing orally disintegrating tablet that has excellent dissolution properties and is miniaturized can be produced with high productivity using general equipment.
Ｌ−カルボシステインは、気道粘膜に含まれる各種ムチンの含量比を正常化し、粘液の粘度を低下させ、また、線毛細胞などの粘膜上皮を修復することにより、粘液線毛輸送系を改善し、貯留物の排泄を促進するため、上気道炎や急性気管支炎の去痰薬として使用されている。 L-carbocysteine improves the mucociliary transport system by normalizing the content ratio of various mucins contained in the airway mucosa, lowering the viscosity of mucus, and repairing mucosal epithelium such as ciliated cells. It is used as an expectorant for upper respiratory tract inflammation and acute bronchitis to promote the excretion of the reservoir.
本発明に使用されるＬ-カルボシステインは、その平均粒子径については特に限定はなく、粉砕品、未粉砕品のいずれも使用することができる。なお、Ｌ−カルボシステインの平均粒子径は、レーザー回折・錯乱法により測定される。錠剤中のＬ−カルボシステインの含有量は、錠剤の小型化の点から錠剤中７５質量％以上が好ましく、さらに好ましくは８０質量％以上であり、製造の点からは９５質量％以下が好ましい。特に好ましくは８５〜９５質量％である。 The average particle diameter of L-carbocysteine used in the present invention is not particularly limited, and either a pulverized product or an unground product can be used. The average particle size of L-carbocysteine is measured by a laser diffraction / confusion method. The content of L-carbocysteine in the tablet is preferably 75% by mass or more, more preferably 80% by mass or more, and preferably 95% by mass or less from the viewpoint of production, from the viewpoint of tablet size reduction. Especially preferably, it is 85-95 mass%.
本発明に使用されるイソマルトは、イソマルチュロースを還元（水素化）することにより得られる糖アルコールであり、６−Ｏ−α−Ｄ−グルコピラノシル−Ｄ−ソルビット（１，６−ＧＰＳ）と１−Ｏ−α−Ｄ−グルコピラノシル−Ｄ−マンニット（１，１−ＧＰＭ）の混合物として知られている。医薬品原料として使用可能なイソマルトは、ＢＥＮＥＯ−Ｐａｌａｔｉｎｉｔ社から購入することが可能であり、１，６−ＧＰＳと１，１−ＧＰＭの組成比率や粒度分布などの物理的特性から様々なタイプの商品が提供されている。例えば、ｇａｌｅｎＩＱ７２０（登録商標）、ｇａｌｅｎＩＱ７２１（登録商標）、ｇａｌｅｎＩＱ８００（登録商標）、ｇａｌｅｎＩＱ８０１（登録商標）、ｇａｌｅｎＩＱ８１０（登録商標）、ｇａｌｅｎＩＱ９６０（登録商標）、ｇａｌｅｎＩＱ９８０（登録商標）、ｇａｌｅｎＩＱ９８１（登録商標）などが挙げられる。また、特許４９４３６０８、特許４３７６４８１に記載されるイソマルトやイソマルト変種も本発明に使用されるイソマルトに含まれる。 Isomalt used in the present invention is a sugar alcohol obtained by reducing (hydrogenating) isomaltulose, and 6-O-α-D-glucopyranosyl-D-sorbitol (1,6-GPS) and Known as a mixture of 1-O-α-D-glucopyranosyl-D-mannitol (1,1-GPM). Isomalt, which can be used as a raw material for pharmaceuticals, can be purchased from BENEO-Palatinit and various types of products based on physical characteristics such as composition ratio and particle size distribution of 1,6-GPS and 1,1-GPM Is provided. For example, galen IQ 720 (registered trademark), galen IQ 721 (registered trademark), galen IQ 800 (registered trademark), galen IQ 801 (registered trademark), galen IQ 810 (registered trademark), galen IQ 960 (registered trademark), galen IQ 980 (registered trademark), galen IQ 981 (registered trademark), etc. Is mentioned. Further, isomalt and isomalt variants described in Japanese Patent Nos. 4943608 and 4376481 are also included in the isomalt used in the present invention.
イソマルトの含有量は、カルボシステイン１００質量部に対して２〜２０質量部が好ましく、さらに好ましくは３〜１２質量部、特に好ましくは５〜１２質量部である。 The content of isomalt is preferably 2 to 20 parts by mass, more preferably 3 to 12 parts by mass, and particularly preferably 5 to 12 parts by mass with respect to 100 parts by mass of carbocysteine.
本発明に使用される崩壊剤は、医薬品製剤の製造に使用可能なものであれば特に限定はなく、各種の崩壊剤が使用できる。このような崩壊剤としては、例えば、医薬品添加物事典［日本医薬品添加剤協会、薬事日報社（２００７年）］に記載されているものを適宜使用できる。例えば、カルボキシメチルセルロースカルシウム、カルボキシメチルセルロースナトリウム、ヒドロキシプロピルセルロース、低置換度ヒドロキシプロピルセルロース、クロスカルメロースナトリウム、メチルセルロースなどのセルロース類やカルボキシメチルスターチナトリウム、部分アルファー化デンプン、ヒドロキシプロピルスターチ、クロスポビドンなどを使用することができ、速やかな崩壊性及び飲用のし易さ（口当たりのよさ）の点からクロスポビドン、低置換度ヒドロキシプロピルセルロースを使用することが好ましい。崩壊剤の配合量は、錠剤中０．５〜１２質量％が好ましく、さらに好ましくは１〜９質量％、特に好ましくは２〜６質量％である。 The disintegrant used for this invention will not be specifically limited if it can be used for manufacture of a pharmaceutical formulation, Various disintegrants can be used. As such a disintegrating agent, for example, those described in Pharmaceutical Additives Encyclopedia [Japan Pharmaceutical Additives Association, Yakuji Nipposha (2007)] can be used as appropriate. For example, carboxymethylcellulose calcium, sodium carboxymethylcellulose, hydroxypropylcellulose, low substituted hydroxypropylcellulose, croscarmellose sodium, methylcellulose and other celluloses, sodium carboxymethyl starch, partially pregelatinized starch, hydroxypropyl starch, crospovidone, etc. It is preferable to use crospovidone and low-substituted hydroxypropylcellulose from the viewpoints of rapid disintegration and ease of drinking (good mouthfeel). The blending amount of the disintegrant is preferably 0.5 to 12% by mass in the tablet, more preferably 1 to 9% by mass, and particularly preferably 2 to 6% by mass.
本発明に用いられる高甘味度甘味剤とは、ショ糖の１０倍以上の甘味度を有する甘味剤である。例えば、アスパルテーム、サッカリンおよびその塩類、グリチルリチン酸およびグリチルリチン酸二カリウム等のグリチルリチン酸の塩類、アセスルファムカリウム、ステビアなどが挙げられ、これらの高甘味度甘味剤は２種以上を用いてもよい。錠剤中の高甘味度甘味剤の含有量は、０．１〜５質量％が好ましく、さらに好ましくは０．５〜３質量％である。 The high-intensity sweetener used in the present invention is a sweetener having a sweetness level 10 times or more that of sucrose. Examples include aspartame, saccharin and salts thereof, glycyrrhizic acid and salts of glycyrrhizic acid such as dipotassium glycyrrhizinate, acesulfame potassium, stevia and the like. Two or more kinds of these high-intensity sweeteners may be used. The content of the high-intensity sweetener in the tablet is preferably 0.1 to 5% by mass, more preferably 0.5 to 3% by mass.
Ｌ−カルボシステインとイソマルトは口腔内崩壊錠中造粒物として配合されていることが好ましい。この造粒物は、流動層造粒法、転動流動層造粒法などにより製造可能であるが、Ｌ−カルボシステインを転動流動層造粒機に仕込み、イソマルトを溶解した液を噴霧し造粒することがより好ましい。また、造粒物の平均粒子径は、５０〜５００μｍが好ましい。 L-carbocysteine and isomalt are preferably blended as granules in the orally disintegrating tablet. This granulated product can be produced by a fluidized bed granulation method, a rolling fluidized bed granulation method or the like, but L-carbocysteine is charged into a rolling fluidized bed granulator and sprayed with a solution in which isomalt is dissolved. It is more preferable to granulate. The average particle diameter of the granulated product is preferably 50 to 500 μm.
圧縮成型は、通常５０〜５００ｋｇ／ｃｍ２の打錠圧で行うが、好ましくは１００〜３５０ｋｇ／ｃｍ２である。 Compression molding is carried out at tableting pressure of usually 50~500kg / cm 2, preferably 100~350kg / cm 2.
本発明において口腔内崩壊錠とは、口腔内で唾液の存在下、咀嚼なしに崩壊する固形医薬製剤であり、好ましくは４０秒以下で崩壊する固形医薬製剤、さらに好ましくは３０秒以下で崩壊する医薬固形製剤である。 In the present invention, an orally disintegrating tablet is a solid pharmaceutical preparation that disintegrates without chewing in the presence of saliva in the oral cavity, preferably a solid pharmaceutical preparation that disintegrates in 40 seconds or less, and more preferably disintegrates in 30 seconds or less. It is a pharmaceutical solid preparation.
実施例１
Ｌ−カルボシステイン（平均粒子径１９μｍ）８００ｇを転動流動層造粒機（ダルトン、ＮＱ−１６０）に仕込み、イソマルト（ＢＥＮＥＯ−Ｐａｌａｔｉｎｉｔ）８０ｇを水２２０ｇに溶解した液を噴霧し造粒、乾燥した（平均粒子径２７４μｍ）。得られた造粒物５５０ｇ、低置換度ヒドロキシプロピルセルロース ＮＢＤ−０２２（信越化学）１５ｇ、及びアスパルテーム（味の素）６ｇを混合後、さらにフマル酸ステアリルナトリウム（ＪＲＳ ＰＨＡＲＭＡ）９ｇを加え混合後、ロータリー打錠機（畑鉄工）を用いて長径１５．５ｍｍ及び短径７．５ｍｍのＬ−カルボシステイン５００ｍｇを含む質量５８０ｍｇの錠剤を製した。得られた錠剤は硬度５．１ｋｇ、口腔内崩壊時間２６秒を示した。
Example 1
800 g of L-carbocysteine (average particle size 19 μm) was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and a solution of 80 g of isomalt (BENEO-Palatinit) dissolved in 220 g of water was sprayed for granulation and drying. (Average particle size 274 μm). After mixing 550 g of the obtained granulated product, 15 g of low-substituted hydroxypropylcellulose NBD-022 (Shin-Etsu Chemical) and 6 g of aspartame (Ajinomoto), 9 g of sodium stearyl fumarate (JRS PHARMA) was added and mixed, and then rotary punching was performed. A tablet with a mass of 580 mg containing 500 mg of L-carbocysteine having a major axis of 15.5 mm and a minor axis of 7.5 mm was produced using a tablet machine (Hatate Iron Works). The obtained tablet had a hardness of 5.1 kg and an oral disintegration time of 26 seconds.
実施例２
Ｌ−カルボシステイン（平均粒子径８１μｍ）８００ｇを転動流動層造粒機（ダルトン、ＮＱ−１６０）に仕込み、イソマルト（ＢＥＮＥＯ−Ｐａｌａｔｉｎｉｔ）８０ｇを水２２０ｇに溶解した液を噴霧し造粒、乾燥した。得られた造粒物５５０ｇ、低置換度ヒドロキシプロピルセルロース ＮＢＤ−０２２（信越化学）１５ｇ、及びアスパルテーム（味の素）５ｇを混合後、さらにフマル酸ステアリルナトリウム（ＪＲＳ ＰＨＡＲＭＡ）６ｇを加え混合後、ロータリー打錠機（畑鉄工）を用いて長径１５．５ｍｍ及び短径７．５ｍｍのＬ−カルボシステイン５００ｍｇを含む質量５７６ｍｇの錠剤を製した。得られた錠剤は硬度７．５ｋｇ、口腔内崩壊時間２６秒を示した。
Example 2
800 g of L-carbocysteine (average particle size 81 μm) was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and a solution prepared by dissolving 80 g of isomalt (BENEO-Palatinit) in 220 g of water was sprayed for granulation and drying. did. After mixing 550 g of the obtained granulated product, 15 g of low-substituted hydroxypropylcellulose NBD-022 (Shin-Etsu Chemical), and 5 g of aspartame (Ajinomoto), 6 g of sodium stearyl fumarate (JRS PHARMA) was added and mixed, followed by rotary punching. A tablet with a mass of 576 mg containing 500 mg of L-carbocysteine having a major axis of 15.5 mm and a minor axis of 7.5 mm was produced using a tablet machine (Hata iron works). The obtained tablet had a hardness of 7.5 kg and an oral disintegration time of 26 seconds.
実施例３
Ｌ−カルボシステイン（平均粒子径８１μｍ）８００ｇを転動流動層造粒機（ダルトン、ＮＱ−１６０）に仕込み、イソマルト（ＢＥＮＥＯ−Ｐａｌａｔｉｎｉｔ）８０ｇを水２２０ｇに溶解した液を噴霧し造粒、乾燥した。得られた造粒物５５０ｇ、低置換度ヒドロキシプロピルセルロース ＮＢＤ−０２２（信越化学）１５ｇ、及びアスパルテーム（味の素）５ｇを混合後、さらにフマル酸ステアリルナトリウム（ＪＲＳ ＰＨＡＲＭＡ）６ｇを加え混合後、ロータリー打錠機（畑鉄工）を用いて長径１５ｍｍ及び短径６．５ｍｍのＬ−カルボシステイン５００ｍｇを含む質量５７６ｍｇの錠剤を製した。得られた錠剤は硬度６．７ｋｇ、口腔内崩壊時間２４秒を示した。
Example 3
800 g of L-carbocysteine (average particle size 81 μm) was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and a solution prepared by dissolving 80 g of isomalt (BENEO-Palatinit) in 220 g of water was sprayed for granulation and drying. did. After mixing 550 g of the obtained granulated product, 15 g of low-substituted hydroxypropylcellulose NBD-022 (Shin-Etsu Chemical), and 5 g of aspartame (Ajinomoto), 6 g of sodium stearyl fumarate (JRS PHARMA) was added and mixed, followed by rotary punching. A tablet having a mass of 576 mg containing 500 mg of L-carbocysteine having a major axis of 15 mm and a minor axis of 6.5 mm was produced using a tablet machine (Hatate Iron Works). The obtained tablet had a hardness of 6.7 kg and an oral disintegration time of 24 seconds.
実施例４
Ｌ−カルボシステイン（平均粒子径８１μｍ）８００ｇを転動流動層造粒機（ダルトン、ＮＱ−１６０）に仕込み、イソマルト（ＢＥＮＥＯ−Ｐａｌａｔｉｎｉｔ）４８ｇを水２２０ｇに溶解した液を噴霧し造粒、乾燥した。得られた造粒物５３０ｇ、低置換度ヒドロキシプロピルセルロース ＮＢＤ−０２２（信越化学）１５ｇ、及びアスパルテーム（味の素）５ｇを混合後、さらにフマル酸ステアリルナトリウム（ＪＲＳ ＰＨＡＲＭＡ）１０ｇを加え混合後、ロータリー打錠機（畑鉄工）を用いて長径１５ｍｍ及び短径６．５ｍｍのＬ−カルボシステイン５００ｍｇを含む質量５６０ｍｇの錠剤を製した。得られた錠剤は硬度７．１ｋｇ、口腔内崩壊時間１７秒を示した。
Example 4
800 g of L-carbocysteine (average particle size 81 μm) was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and a solution obtained by dissolving 48 g of isomalt (BENEO-Palatinit) in 220 g of water was sprayed to granulate and dry. did. After mixing 530 g of the resulting granulated product, 15 g of low-substituted hydroxypropylcellulose NBD-022 (Shin-Etsu Chemical) and 5 g of aspartame (Ajinomoto), 10 g of sodium stearyl fumarate (JRS PHARMA) was added and mixed, and then rotary punching was performed. A tablet having a mass of 560 mg containing 500 mg of L-carbocysteine having a major axis of 15 mm and a minor axis of 6.5 mm was produced using a tablet machine (Hatate Iron Works). The obtained tablet had a hardness of 7.1 kg and an oral disintegration time of 17 seconds.
実施例５
Ｌ−カルボシステイン（平均粒子径８１μｍ）３０００ｇを転動流動層造粒機（フロイント産業、ＳＦＣ−５）に仕込み、イソマルト（ＢＥＮＥＯ−Ｐａｌａｔｉｎｉｔ）１８０ｇを水８２５ｇに溶解した液を噴霧し造粒、乾燥した。得られた造粒物５３０ｇ、低置換度ヒドロキシプロピルセルロース ＮＢＤ−０２２（信越化学）１５ｇ、及びアスパルテーム（味の素）１０ｇを混合後、さらにフマル酸ステアリルナトリウム（ＰＨＡＲＭＡ ＴＲＡＮＳ ＳＡＮＡＱ ＡＧ）１０ｇを加え混合後、ロータリー打錠機（畑鉄工）を用いて打錠圧０．５ｋＮにて長径１５ｍｍ及び短径６．５ｍｍのＬ−カルボシステイン５００ｍｇを含む質量５６５ｍｇの錠剤を製した。得られた錠剤は硬度７．２ｋｇ、口腔内崩壊時間２４秒を示した。
Example 5
L-carbocysteine (average particle size 81 μm) 3000 g was charged into a rolling fluidized bed granulator (Freund Sangyo, SFC-5), and a solution obtained by dissolving 180 g of isomalt (BENEO-Palatinit) in water 825 g was granulated. Dried. After mixing 530 g of the obtained granulated product, 15 g of low-substituted hydroxypropylcellulose NBD-022 (Shin-Etsu Chemical), and 10 g of aspartame (Ajinomoto), 10 g of sodium stearyl fumarate (PHARMA TRANS SANAQ AG) was added and mixed. A tablet with a mass of 565 mg containing 500 mg of L-carbocysteine having a major axis of 15 mm and a minor axis of 6.5 mm was produced at a tableting pressure of 0.5 kN using a rotary tableting machine (Hatate Iron Works). The obtained tablet had a hardness of 7.2 kg and an oral disintegration time of 24 seconds.
実施例６
Ｌ−カルボシステイン（平均粒子径８１μｍ）３０００ｇを転動流動層造粒機（フロイント産業、ＳＦＣ−５）に仕込み、イソマルト（ＢＥＮＥＯ−Ｐａｌａｔｉｎｉｔ）１８０ｇを水８２５ｇに溶解した液を噴霧し造粒、乾燥した。得られた造粒物３１８ｇ、低置換度ヒドロキシプロピルセルロース ＮＢＤ−０２２（信越化学）１２ｇ、アスパルテーム（味の素）６ｇ、及びピーチパウダーフレーバー（小林香料）０．３ｇを混合後、さらにフマル酸ステアリルナトリウム（ＰＨＡＲＭＡ ＴＲＡＮＳ ＳＡＮＡＱ ＡＧ）７．２ｇを加え混合後、ロータリー打錠機（畑鉄工）を用いて長径１５．５ｍｍ及び短径７．５ｍｍのＬ−カルボシステイン５００ｍｇを含む質量５７２ｍｇの錠剤を製した。得られた錠剤は硬度５．０ｋｇ、口腔内崩壊時間２６秒を示した。
Example 6
L-carbocysteine (average particle size 81 μm) 3000 g was charged into a rolling fluidized bed granulator (Freund Sangyo, SFC-5), and a solution obtained by dissolving 180 g of isomalt (BENEO-Palatinit) in water 825 g was granulated. Dried. After mixing 318 g of the obtained granulated product, 12 g of low-substituted hydroxypropylcellulose NBD-022 (Shin-Etsu Chemical), 6 g of aspartame (Ajinomoto) and 0.3 g of peach powder flavor (Kobayashi fragrance), sodium stearyl fumarate ( (PHARMA TRANS SANAQ AG) (7.2 g) was added and mixed, and then a tablet with a mass of 572 mg containing L-carbocysteine (500 mg) having a major axis of 15.5 mm and a minor axis of 7.5 mm was produced using a rotary tableting machine (Hatateko). The obtained tablet had a hardness of 5.0 kg and an oral disintegration time of 26 seconds.
実施例７
Ｌ−カルボシステイン（平均粒子径８１μｍ）３０００ｇを転動流動層造粒機（フロイント産業、ＳＦＣ−５）に仕込み、イソマルト（ＢＥＮＥＯ−Ｐａｌａｔｉｎｉｔ）１８０ｇを水８２５ｇに溶解した液を噴霧し造粒、乾燥した。得られた造粒物３１８ｇ、低置換度ヒドロキシプロピルセルロース ＮＢＤ−０２２（信越化学）１２ｇ、アスパルテーム（味の素）６ｇ、及びピーチパウダーフレーバー（小林香料）０．３ｇを混合後、さらにショ糖脂肪酸エステル（三菱化学フーズ）７．２ｇを加え混合後、ロータリー打錠機（畑鉄工）を用いて長径１５．５ｍｍ及び短径７．５ｍｍのＬ−カルボシステイン５００ｍｇを含む質量５７２ｍｇの錠剤を製した。得られた錠剤は硬度６．０ｋｇ、口腔内崩壊時間２４秒を示した。
Example 7
L-carbocysteine (average particle size 81 μm) 3000 g was charged into a rolling fluidized bed granulator (Freund Sangyo, SFC-5), and a solution obtained by dissolving 180 g of isomalt (BENEO-Palatinit) in water 825 g was granulated. Dried. After mixing 318 g of the obtained granulated product, 12 g of low-substituted hydroxypropylcellulose NBD-022 (Shin-Etsu Chemical), 6 g of aspartame (Ajinomoto) and 0.3 g of peach powder flavor (Kobayashi fragrance), sucrose fatty acid ester ( After adding and mixing 7.2 g (Mitsubishi Chemical Foods), tablets with a mass of 572 mg containing 500 mg of L-carbocysteine having a major axis of 15.5 mm and a minor axis of 7.5 mm were produced using a rotary tableting machine (Hatate Iron Works). The obtained tablet exhibited a hardness of 6.0 kg and an oral disintegration time of 24 seconds.
比較例１
Ｌ−カルボシステイン（平均粒子径１９μｍ）８００ｇを転動流動層造粒機（ダルトン、ＮＱ−１６０）に仕込み、トレハロース（旭化成ケミカルズ）８０ｇを水２２０ｇに溶解した液を噴霧し造粒した。乾燥後、この造粒物についてロータリー打錠機（畑鉄工）を用いて打錠圧１．０ｋＮにて長径１５．５ｍｍ及び短径７．５ｍｍのＬ−カルボシステイン５００ｍｇを含む質量５５０ｍｇの錠剤を製した。得られた錠剤の物性は硬度１．６ｋｇであり、十分な硬度を得ることはできなかった。
なお、錠剤硬度を上げるために打錠圧を変更したところ、打錠障害（キャッピング）が発生し成錠できなかった。
Comparative Example 1
800 g of L-carbocysteine (average particle size 19 μm) was charged into a rolling fluidized bed granulator (Dalton, NQ-160), and a solution obtained by dissolving 80 g of trehalose (Asahi Kasei Chemicals) in 220 g of water was sprayed and granulated. After drying, a 550 mg tablet containing 500 mg of L-carbocysteine having a major axis of 15.5 mm and a minor axis of 7.5 mm at a tableting pressure of 1.0 kN using a rotary tableting machine (Hata iron works) is used for this granulated product. Made. The physical properties of the obtained tablets were 1.6 kg in hardness, and sufficient hardness could not be obtained.
In addition, when the tableting pressure was changed to increase tablet hardness, a tableting failure (capping) occurred, and the tablet could not be locked.
比較例２
トレハロース（旭化成ケミカルズ）４０ｇを水１１６０ｇに溶解した液に５０％粒子径５１μｍのＬ−カルボシステイン４００ｇを懸濁し、スプレードライヤー（ニロアトマイザー、ＭＭ−０１）で給気温度２２０℃、排気温度１２０℃、スプレー圧０．０２ＭＰａで噴霧乾燥造粒して造粒物を得た。この造粒物５５０ｇ、アスパルテーム（味の素）１５ｇを混合後、ステアリン酸マグネシウム植物性（太平化学産業）１０ｇを加え混合後、単発打錠機（岡田精工）を用いて打錠圧０．１〜０．２ｋＮにて錠径１４．５ｍｍのカルボシステイン５００ｍｇを含む質量５７５ｍｇの打錠品を製した。この打錠品を２５℃、湿度７５％に設定した恒温恒湿器（タバイ）に２４時間保存した後、シリカゲルを充填したデシケーター内で４８時間乾燥して錠剤を得た。得られた錠剤の物性は、硬度７．２ｋｇ、口腔内崩壊時間５２秒と５０％粒子径５１μｍのＬ−カルボシステインを使用した場合適度な物性は得られなかった。
Comparative Example 2
400 g of L-carbocysteine having a 50% particle size of 51 μm is suspended in a solution of 40 g of trehalose (Asahi Kasei Chemicals) in 1160 g of water, and the supply temperature is 220 ° C. and the exhaust temperature is 120 ° C. with a spray dryer (Niro atomizer, MM-01). The granulated product was obtained by spray-drying granulation at a spray pressure of 0.02 MPa. After mixing 550 g of this granulated product and 15 g of aspartame (Ajinomoto), 10 g of magnesium stearate plant (Taihei Chemical Industry) was added and mixed, and the tableting pressure was 0.1-0 using a single tableting machine (Okada Seiko). A tableted product having a mass of 575 mg containing 500 mg of carbocysteine having a tablet diameter of 14.5 mm at 2 kN was produced. The tableted product was stored for 24 hours in a constant temperature and humidity chamber (tabai) set at 25 ° C. and humidity 75%, and then dried for 48 hours in a desiccator filled with silica gel to obtain a tablet. The physical properties of the obtained tablets were not obtained when L-carbocysteine having a hardness of 7.2 kg, an oral disintegration time of 52 seconds and a 50% particle size of 51 μm was used.
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