JP6100939B2 - Method for improving hygroscopicity / fluidity of solid preparation for internal use, solid preparation for internal use with improved hygroscopicity / flowability, and method for producing the solid preparation for internal use - Google Patents
Method for improving hygroscopicity / fluidity of solid preparation for internal use, solid preparation for internal use with improved hygroscopicity / flowability, and method for producing the solid preparation for internal use Download PDFInfo
- Publication number
- JP6100939B2 JP6100939B2 JP2016035699A JP2016035699A JP6100939B2 JP 6100939 B2 JP6100939 B2 JP 6100939B2 JP 2016035699 A JP2016035699 A JP 2016035699A JP 2016035699 A JP2016035699 A JP 2016035699A JP 6100939 B2 JP6100939 B2 JP 6100939B2
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- Japan
- Prior art keywords
- solid preparation
- internal use
- carnitine
- dimethylpolysiloxane
- fluidity
- Prior art date
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Images
Description
本発明は、内服用固形製剤の吸湿性及び／又は流動性の改善方法、吸湿性及び／又は流動性が改善されてなる内服用固形製剤、さらに該内服用固形製剤の製造法に関する。 The present invention relates to a method for improving hygroscopicity and / or fluidity of a solid preparation for internal use, a solid preparation for internal use having improved hygroscopicity and / or fluidity, and a method for producing the solid preparation for internal use.
カルニチン又はその塩は、消化管機能低下のみられる慢性胃炎に有効な消化機能賦活亢進剤として使用されている薬物であり、胃腸薬として一般に用いられている。また、カルニチン又はその塩は、生体内において長鎖脂肪酸を細胞内のミトコンドリア内に運搬する役割を有しており、中性脂肪の代謝に必要な物質で、ダイエットのためのサプリメント等にも利用されている。 Carnitine or a salt thereof is a drug that is used as a digestive function activation enhancer that is effective for chronic gastritis with decreased gastrointestinal function, and is generally used as a gastrointestinal drug. Carnitine or its salt has a role in transporting long-chain fatty acids into the mitochondria in cells in the body, and is a substance necessary for the metabolism of neutral fat. It is also used for dietary supplements, etc. Has been.
しかしながら、カルニチンやその塩は吸湿性や潮解性を有することから、固形製剤を製造する場合においては、カルニチンやその塩に起因する染み出しによる経時的な製剤同士の付着や、製剤の変色、味の変化等の問題が生ずる。このため、様々な製剤化検討がこれまでになされてきている。 However, since carnitine and its salts have hygroscopicity and deliquescence, when manufacturing a solid preparation, adhesion of preparations over time due to exudation due to carnitine and its salts, discoloration of the preparation, taste Problems such as changes in For this reason, various preparation studies have been made so far.
例えば、塩化カルニチンを吸着性物質に吸着せしめてなる固形物（特許文献１）、Ｌ−カルニチン、油性成分、賦形剤、及び滑沢剤を含む圧縮成形体であって、成形体１００重量部中に、Ｌ−カルニチン粉末６０〜９０重量％及び融点４０℃以上の油性成分１０〜４０重量％から構成され表面に油性成分を被覆してなる平均粒径１０〜１０００μｍのＬ−カルニチン粉末を１１〜６７重量部含むＬ−カルニチン圧縮成形体（特許文献２）、カルニチン含有固形物をシェラック膜でコーティングした後、酵母細胞壁膜で更にコーティングしてなるカルニチン含有製品（特許文献３）、カルニチン類、硬化油及びマンニトールを含有する固形製剤（特許文献４）等が知られている。 For example, a compression molded body containing a solid material (Patent Document 1) obtained by adsorbing carnitine chloride to an adsorbent substance, L-carnitine, an oil component, an excipient, and a lubricant, and 100 parts by weight of the molded body 11 L-carnitine powder having an average particle diameter of 10 to 1000 μm, which is composed of 60 to 90% by weight of L-carnitine powder and 10 to 40% by weight of an oily component having a melting point of 40 ° C. or more and having a surface coated with the oily component. L-carnitine compression molded body containing ~ 67 parts by weight (Patent Document 2), carnitine-containing product (Patent Document 3) obtained by coating a carnitine-containing solid material with a shellac membrane and further coating with a yeast cell wall membrane, Solid preparations containing hydrogenated oil and mannitol (Patent Document 4) are known.
しかしながらこれらの固形製剤の製造には、カルニチンの吸着性物質への吸着や被覆、コーティング、油成分の添加等を要することによる工程の複雑化、製造ラインの専用化等の問題があり、実生産を行う上で満足のいくものではなかった。 However, the production of these solid preparations has problems such as complicated processes due to the need to adsorb and coat carnitine on adsorbing substances, coating, and the addition of oil components, and dedicated production lines. Was not satisfactory in doing.
ジメチルポリシロキサンは、シリコンの一種であり、界面活性剤、離型剤、表面処理剤等として、化粧料、皮膚外用剤、経口剤等に使用されている。特に、経口剤の分野では、滑沢剤、コーティング剤、消泡剤等添加剤としてや、胃腸管内のガスに起因する腹部症状（げっぷ、胃部膨満感、鼓腸等）等の治療又は予防に用いられている。 Dimethylpolysiloxane is a kind of silicon, and is used in cosmetics, external preparations for skin, oral preparations and the like as surfactants, mold release agents, surface treatment agents and the like. In particular, in the field of oral preparations, as additives such as lubricants, coating agents, antifoaming agents, and for the treatment or prevention of abdominal symptoms (burp, stomach fullness, flatulence, etc.) caused by gas in the gastrointestinal tract It is used.
本発明が解決する課題は、内服用固形製剤において、製剤の吸湿性と経時的流動性の改善である。特に、内服用固形製剤の吸湿性と経時的流動性の改善剤を提供することである。さらに、カルニチンまたはその塩を含有する内服用固形製剤の吸湿性と経時的流動性の改善である。 The problem to be solved by the present invention is to improve the hygroscopicity and fluidity over time of a solid preparation for internal use. In particular, it is to provide an agent for improving hygroscopicity and fluidity over time of a solid preparation for internal use. Furthermore, it is improvement of the hygroscopic property and fluidity | liquidity with time of the solid preparation for internal use containing a carnitine or its salt.
本発明者は、内服用固形製剤の吸湿性と経時的流動性の改善剤として、ジメチルポリシロキサンまたはその誘導体が有効であることを見出し、本発明を完成した。すなわち、本発明は以下からなる；
１．（Ａ）カルニチン又はその塩から選択される少なくとも一つの化合物と、（Ｂ）ジメチルポリシロキサン又はその誘導体から選択される少なくとも一つの化合物を含有する内服用固形製剤。
２．（Ｂ）ジメチルポリシロキサン又はその誘導体から選択される少なくとも一つの化合物が、（Ａ）カルニチン又はその塩を含有する内服用固形製剤の吸湿抑制量及び／又は流動性改善量が含有されてなる前項１の内服用固形製剤。
３．（Ｂ）ジメチルポリシロキサン又はその誘導体から選択される少なくとも一つの化合物の含有量が、（Ａ）カルニチン又はその塩から選択される少なくとも一つの化合物の１００重量部に対し、５〜１５０重量部である前項１又は２の内服用固形製剤。
４．（Ｂ）ジメチルポリシロキサン又はその誘導体から選択される少なくとも一つの化合物の含有量が、固形製剤全重量の１〜２０％重量部である前項１〜３のいずれか一に記載の内服用固形製剤。
５．（Ａ）カルニチン又はその塩から選択される少なくとも一つの化合物が、カルニチン塩化物である前項１〜４のいずれか一に記載の内服用固形製剤。
６．（Ｂ）ジメチルポリシロキサン又はその誘導体から選択される少なくとも一つの化合物が、平均ｎ値が２〜６５０の直鎖状（ＣＨ３）３Ｓｉ〔（ＣＨ３）２ＳｉＯ〕ｎＯＳｉ（ＣＨ３）３である前項１〜５のいずれか一に記載の内服用固形製剤。
７．固形製剤が、錠剤、散剤、顆粒剤、細粒剤、粉剤、カプセル剤のいずれか一である前項１〜６のいずれか一に記載の内服用固形製剤。
８．（Ｂ）ジメチルポリシロキサン又はその誘導体から選択される少なくとも一つの化合物を含有することを特徴とする内服用固形製剤の吸湿抑制及び／又は流動性改善方法。
９．内服用固形製剤が、（Ａ）カルニチン又はその塩から選択される少なくとも一つの化合物を含有することを特徴とする前項８に記載の内服用固形製剤の吸湿抑制及び／又は流動性改善方法。
１０．（Ｂ）ジメチルポリシロキサン又はその誘導体から選択される少なくとも一つの化合物を配合することを特徴とする吸湿抑制及び／又は流動性改善された内服用固形製剤の製造方法。
１１．内服用固形製剤が、（Ａ）カルニチン又はその塩から選択される少なくとも一つの化合物を含有することを特徴とする前項１０に記載の吸湿抑制及び／又は流動性改善された内服用固形製剤の製造方法。
１２．（Ｂ）ジメチルポリシロキサン又はその誘導体から選択される少なくとも一つの化合物を含有する内服用固形製剤の吸湿抑制及び／又は流動性改善剤。
１３．内服用固形製剤が、（Ａ）カルニチン又はその塩から選択される少なくとも一つの化合物を含有することを特徴とする前項１２に記載の内服用固形製剤の吸湿抑制及び／又は流動性改善剤。
The present inventor has found that dimethylpolysiloxane or a derivative thereof is effective as an agent for improving hygroscopicity and fluidity over time of a solid preparation for internal use, and has completed the present invention. That is, the present invention comprises:
1. (A) A solid preparation for internal use containing at least one compound selected from carnitine or a salt thereof and (B) at least one compound selected from dimethylpolysiloxane or a derivative thereof.
2. (B) The preceding paragraph wherein at least one compound selected from dimethylpolysiloxane or a derivative thereof contains (A) a moisture absorption suppression amount and / or fluidity improvement amount of a solid preparation for internal use containing carnitine or a salt thereof. 1. A solid preparation for internal use.
3. (B) The content of at least one compound selected from dimethylpolysiloxane or a derivative thereof is 5 to 150 parts by weight with respect to 100 parts by weight of at least one compound selected from (A) carnitine or a salt thereof. 3. A solid preparation for internal use according to 1 or 2 above.
4). (B) The solid preparation for internal use as described in any one of 1 to 3 above, wherein the content of at least one compound selected from dimethylpolysiloxane or a derivative thereof is 1 to 20% by weight of the total weight of the solid preparation .
5. (A) The solid preparation for internal use as described in any one of 1 to 4 above, wherein at least one compound selected from carnitine or a salt thereof is carnitine chloride.
6). (B) At least one compound selected from dimethylpolysiloxane or a derivative thereof is a linear (CH 3 ) 3 Si [(CH 3 ) 2 SiO] n OSi (CH 3 ) having an average n value of 2 to 650 3. The solid preparation for internal use according to any one of 1 to 5 above, which is 3 .
7). The solid preparation for internal use according to any one of the preceding items 1 to 6, wherein the solid preparation is any one of tablets, powders, granules, fine granules, powders, and capsules.
8). (B) A method for suppressing moisture absorption and / or improving fluidity of a solid preparation for internal use, comprising at least one compound selected from dimethylpolysiloxane or a derivative thereof.
9. 9. The method for suppressing moisture absorption and / or improving fluidity of a solid preparation for internal use according to 8 above, wherein the solid preparation for internal use contains (A) at least one compound selected from carnitine or a salt thereof.
10. (B) A method for producing a solid preparation for internal use having improved moisture absorption and / or improved fluidity, comprising blending at least one compound selected from dimethylpolysiloxane or a derivative thereof.
11. The solid preparation for internal use according to
12 (B) A moisture absorption inhibitor and / or fluidity improver for a solid preparation for internal use containing at least one compound selected from dimethylpolysiloxane or a derivative thereof.
13. 13. The solid absorption preparation for internal use according to item 12 above, wherein the solid preparation for internal use contains at least one compound selected from (A) carnitine or a salt thereof.
本発明は、内服用固形製剤の吸湿性と経時的流動性を顕著に改善することに成功した。
特に、カルニチン又はその塩を含有する内服用固形製剤の吸湿性と経時的流動性の改善剤を提供する。すなわち、カルニチン又はその塩とジメチルポリシロキサン又はその誘導体とを組み合わせることにより、カルニチン又はその塩を含有する内服用固形製剤の吸湿性が低減し、かつ、カルニチン又はその塩を含有する内服用固形製剤の経時的流動性の変化を抑制する。カルニチン又はその塩を含有する内服用固形製剤自体の特性が改善され、カルニチン又はその塩を含有する固形製剤の品質変化が抑制され、錠剤、顆粒剤等の固形製剤を調製しやすくなる。
The present invention succeeded in remarkably improving the hygroscopicity and fluidity over time of a solid preparation for internal use.
In particular, the present invention provides an agent for improving hygroscopicity and fluidity over time of a solid preparation for internal use containing carnitine or a salt thereof. That is, by combining carnitine or a salt thereof and dimethylpolysiloxane or a derivative thereof, the hygroscopicity of a solid preparation for internal use containing carnitine or a salt thereof is reduced, and a solid preparation for internal use containing carnitine or a salt thereof Inhibits changes in fluidity over time. The characteristics of the solid preparation for internal use containing carnitine or a salt thereof are improved, the quality change of the solid preparation containing carnitine or a salt thereof is suppressed, and a solid preparation such as a tablet or granule can be easily prepared.
本発明の一は、（Ａ）カルニチン又はその塩から選択される少なくとも一つの化合物と、（Ｂ）ジメチルポリシロキサン又はその誘導体から選択される少なくとも一つの化合物を含有する内服用固形製剤からなる。さらに本発明は、（Ｂ）ジメチルポリシロキサン又はその誘導体から選択される少なくとも一つの化合物を含有することを特徴とする内服用固形製剤の吸湿抑制及び／又は流動性改善方法からなり、特に、（Ｂ）ジメチルポリシロキサン又はその誘導体から選択される少なくとも一つの化合物を配合してなる（Ａ）カルニチン又はその塩から選択される少なくとも一つの化合物を含有する内服用固形製剤の吸湿抑制及び／又は流動性改善方法からなる。加えて、本発明は、（Ｂ）ジメチルポリシロキサン又はその誘導体から選択される少なくとも一つの化合物を含有することを特徴とする吸湿抑制及び／又は流動性改善された内服用固形製剤の製造方法からなり、特に、（Ｂ）ジメチルポリシロキサン又はその誘導体から選択される少なくとも一つの化合物を配合してなる（Ａ）カルニチン又はその塩から選択される少なくとも一つの化合物を含有する吸湿抑制及び／又は流動性改善された内服用固形製剤の製造方法からなる。さらに、本発明は、（Ｂ）ジメチルポリシロキサン又はその誘導体から選択される少なくとも一つの化合物を含有する内服用固形製剤の吸湿抑制及び／又は流動性改善剤からなり、特に、内服用固形製剤が、（Ａ）カルニチン又はその塩から選択される少なくとも一つの化合物と、（Ｂ）ジメチルポリシロキサン又はその誘導体から選択される少なくとも一つの化合物を含有する内服用固形製剤の吸湿抑制及び／又は流動性改善剤からなる。 One aspect of the present invention comprises a solid preparation for internal use containing (A) at least one compound selected from carnitine or a salt thereof and (B) at least one compound selected from dimethylpolysiloxane or a derivative thereof. Furthermore, the present invention comprises (B) a method for suppressing moisture absorption and / or improving fluidity of a solid preparation for internal use, comprising at least one compound selected from dimethylpolysiloxane or a derivative thereof, B) Hygroscopic inhibition and / or flow of a solid preparation for internal use containing at least one compound selected from (A) carnitine or a salt thereof obtained by blending at least one compound selected from dimethylpolysiloxane or derivatives thereof It consists of a sex improvement method. In addition, the present invention includes (B) a method for producing a solid preparation for internal use having improved moisture absorption and / or improved fluidity, which comprises at least one compound selected from dimethylpolysiloxane or a derivative thereof. In particular, (B) at least one compound selected from (B) dimethylpolysiloxane or a derivative thereof, and (A) moisture absorption suppression and / or flow containing at least one compound selected from carnitine or a salt thereof. It comprises a method for producing a solid preparation for internal use with improved properties. Furthermore, the present invention comprises (B) a moisture absorption inhibiting and / or fluidity improving agent for a solid preparation for internal use containing at least one compound selected from dimethylpolysiloxane or a derivative thereof. (A) Hygroscopic inhibition and / or fluidity of a solid preparation for internal use containing at least one compound selected from carnitine or a salt thereof and (B) at least one compound selected from dimethylpolysiloxane or a derivative thereof It consists of an improving agent.
本発明のカルニチン又はその塩〔以下（Ａ）成分と記すことがある〕は、カルニチンの種類は特に限定されず、市販のものを使用することもできるし、公知又は新規な方法で製造したカルニチンを使用することもできる。例えば、カルニチンの光学活性体の種類は限定されず、ラセミ体のカルニチンを使用することもできるし、Ｄ体又はＬ体が使用できるし、異なる光学活性体を２種以上組み合わせても良い。また使用するカルニチンの性状も限定されるものではなく、結晶状のものも使用できる。カルニチンは、遊離体であっても、その食品学的又は薬学的に許容可能な塩の形態であってもよい。そのようなカルニチンの塩は、金属塩、有機酸塩、無機酸塩等のいずれでもよく、例えば、ナトリウム、カリウム、カルシウム、マグネシウム、亜鉛等の金属との塩、アンモニウム塩、塩酸塩、硫酸塩、リン酸塩、酢酸塩、プロピオン酸塩、乳酸塩、酒石酸塩、クエン酸塩、コハク酸塩、フマル酸塩、マレイン酸塩等があるが、これらに限定されるものではない。本発明においては、広く市販されており容易に入手できる点でＬ−カルニチン及びカルニチン塩化物が最適である。 The carnitine of the present invention or a salt thereof (hereinafter sometimes referred to as the component (A)) is not particularly limited in the kind of carnitine, and a commercially available one can be used, or carnitine produced by a known or novel method. Can also be used. For example, the type of optically active form of carnitine is not limited, racemic carnitine can be used, D form or L form can be used, and two or more different optically active forms may be combined. Further, the properties of carnitine used are not limited, and crystalline ones can also be used. Carnitine may be in the free form or in the form of a pharmaceutically or pharmaceutically acceptable salt thereof. Such carnitine salts may be any of metal salts, organic acid salts, inorganic acid salts, etc., for example, salts with metals such as sodium, potassium, calcium, magnesium, zinc, ammonium salts, hydrochlorides, sulfates. , Phosphate, acetate, propionate, lactate, tartrate, citrate, succinate, fumarate, maleate and the like, but are not limited thereto. In the present invention, L-carnitine and carnitine chloride are most suitable because they are widely commercially available and can be easily obtained.
本発明のジメチルポリシロキサン又はその誘導体（以下（Ｂ）成分と記すことがある）は、次の(化１)で表され、式中のＲがメチル基のものがジメチルポリシロキサンであり、ジメチルポリシロキサンの誘導体とは、ジメチルポリシロキサンのメチル基の一部をフェニル基に換えたもの、水素に換えたもの、炭素数が２以上のアルキル基に換えたもの、エポキシ基、カルボキシル基、アミノ基、水酸基等の置換基を有するアルキル基に換えたもの等が挙げられる。
(化１)（Ｒ）３−Ｓｉ−〔ＯＳｉ（Ｒ）２〕ｎ−ＯＳｉ（Ｒ）３
（式中、ｎは１〜１０００の整数を示す）
好適には、平均重縮合度（ｎ）が２〜６５０、より好ましくは６７〜２２８の範囲にあるものである。また、第１４改正日本薬局方 一般試験法 ４５．粘度測定法 第一法 毛細管粘度計法に従い、２５℃における粘度を測定するとき、好適には２〜５０００mm2/s、より好ましくは９５〜１０５０mm2/sの範囲にあるものである。ジメチルポリシロキサン又はその誘導体は、常温において、通常、液状である。
The dimethylpolysiloxane of the present invention or a derivative thereof (hereinafter sometimes referred to as component (B)) is represented by the following (Chemical Formula 1), wherein R is a methyl group, and dimethylpolysiloxane is Polysiloxane derivatives include those in which part of the methyl group of dimethylpolysiloxane is replaced with a phenyl group, a hydrogen group, an alkyl group having 2 or more carbon atoms, an epoxy group, a carboxyl group, an amino group And those substituted with an alkyl group having a substituent such as a group and a hydroxyl group.
(Chemical Formula 1) (R) 3 —Si— [OSi (R) 2 ] n —OSi (R) 3
(In the formula, n represents an integer of 1 to 1000)
Preferably, the average polycondensation degree (n) is in the range of 2 to 650, more preferably 67 to 228. In addition, the 14th revised Japanese Pharmacopoeia General Test Method 45. Viscosity Measurement Method First Method When the viscosity at 25 ° C. is measured according to the capillary viscometer method, it is preferably in the range of 2 to 5000 mm 2 / s, more preferably 95 to 1050 mm 2 / s. Dimethylpolysiloxane or a derivative thereof is usually liquid at room temperature.
本発明の内服用固形製剤、内服用固形製剤の吸湿抑制及び／又は流動性改善方法、吸湿抑制及び／又は流動性改善された内服用固形製剤の製造方法、並びに内服用固形製剤の吸湿抑制及び／又は流動性改善剤において、（Ｂ）ジメチルポリシロキサン又はその誘導体から選択される少なくとも一つの化合物と（Ａ）カルニチン又はその塩の含有量は、（Ａ）カルニチン又はその塩を含有する内服用固形製剤の吸湿抑制量及び／又は流動性改善量の（Ｂ）ジメチルポリシロキサン又はその誘導体が配合される。
吸湿抑制量とは、例えば、内服用固形製剤からなる試験粉体を用いて、75%RH, 25℃恒湿デシケータで保存し、経時的にサンプルを取り出し、その際の赤外水分値〔例えば、赤外水分計 FD-720（ケット科学研究所製）を使用〕を測定し、試験粉体中の水分含有量の変化を評価することで判定される。流動性改善量は、例えば、内服用固形製剤からなる試験粉体を用いて、75%RH, 25℃の恒湿デシケータで保存し、その際の安息角を測定することによって判定される。同様に、公知の内服用固形製剤の吸湿性の評価手段、流動性の評価手段は適応可能である。
Solid preparation for internal use of the present invention, method for suppressing moisture absorption and / or improving fluidity of solid preparation for internal use, method for producing solid preparation for internal use with improved moisture absorption and / or fluidity, and suppressing moisture absorption of solid preparation for internal use and In the fluidity improver, the content of (B) at least one compound selected from dimethylpolysiloxane or a derivative thereof and (A) carnitine or a salt thereof is an internal use containing (A) carnitine or a salt thereof (B) Dimethylpolysiloxane or a derivative thereof in an amount of suppressing moisture absorption and / or improving fluidity of the solid preparation is blended.
The amount of moisture absorption suppression is, for example, using a test powder consisting of a solid preparation for internal use, stored in a 75% RH, 25 ° C. constant humidity desiccator, taking out a sample over time, and the infrared moisture value at that time (for example, , Using an infrared moisture meter FD-720 (manufactured by Kett Science Laboratory)] and measuring the change in the moisture content in the test powder. The fluidity improvement amount is determined by, for example, storing a test powder comprising a solid preparation for internal use in a constant humidity desiccator at 75% RH and 25 ° C., and measuring the angle of repose at that time. Similarly, known hygroscopic evaluation means and fluidity evaluation means of a solid preparation for internal use can be applied.
本発明の内服用固形製剤、内服用固形製剤の吸湿抑制及び／又は流動性改善方法、吸湿抑制及び／又は流動性改善された内服用固形製剤の製造方法、並びに内服用固形製剤の吸湿抑制及び／又は流動性改善剤において、（Ｂ）ジメチルポリシロキサン又はその誘導体から選択される少なくとも一つの化合物と（Ａ）カルニチン又はその塩の含有量は、（Ａ）カルニチン又はその塩から選択される少なくとも一つの化合物の１００重量部に対し、（Ｂ）ジメチルポリシロキサン又はその誘導体から選択される少なくとも一つの化合物を、１〜１２００重量部、好適には３〜１０００重量部、より好適には４〜５００重量部、さらに好適には５〜１５０重量部である。（Ｂ）ジメチルポリシロキサン又はその誘導体の量は、多いほど吸湿抑制効果及び流動性改善効果がよいが、主成分である（Ａ）カルニチン又はその塩を含有する内服用固形製剤に対して、必要最小限に添加することが経済性の観点から好ましい。 Solid preparation for internal use of the present invention, method for suppressing moisture absorption and / or improving fluidity of solid preparation for internal use, method for producing solid preparation for internal use with improved moisture absorption and / or fluidity, and suppressing moisture absorption of solid preparation for internal use and In the fluidity improver, the content of (B) at least one compound selected from dimethylpolysiloxane or a derivative thereof and (A) carnitine or a salt thereof is at least selected from (A) carnitine or a salt thereof. 1 to 1200 parts by weight, preferably 3 to 1000 parts by weight, more preferably 4 to 4 parts by weight of at least one compound selected from (B) dimethylpolysiloxane or a derivative thereof with respect to 100 parts by weight of one compound. 500 parts by weight, more preferably 5 to 150 parts by weight. (B) The more the amount of dimethylpolysiloxane or its derivative, the better the moisture absorption suppressing effect and the fluidity improving effect, but it is necessary for the solid preparation for internal use containing (A) carnitine or its salt as the main component. Addition to the minimum is preferable from the viewpoint of economy.
本発明の内服用固形製剤、内服用固形製剤の吸湿抑制及び／もしくは流動性改善方法、吸湿抑制及び／もしくは流動性改善された内服用固形製剤の製造方法、及び内服用固形製剤の吸湿抑制及び／もしくは流動性改善剤において、（Ｂ）ジメチルポリシロキサン又はその誘導体から選択される少なくとも一つの化合物の内服用固形製剤の全重量に対する比率は、前記吸湿抑制有効量及び／又は流動性改善有効量から導き出されるが、一般的には、内服用固形製剤全重量の１〜２０重量％、好適には２〜１６重量％、より好適には２〜１５重量％である。 Solid preparation for internal use of the present invention, method for suppressing moisture absorption and / or improving fluidity of solid preparation for internal use, method for producing solid preparation for internal use having improved moisture absorption and / or fluidity, and suppressing moisture absorption of solid preparation for internal use and In the fluidity improver, (B) the ratio of at least one compound selected from dimethylpolysiloxane or a derivative thereof to the total weight of the solid preparation for internal use is an effective amount for suppressing moisture absorption and / or an effective amount for improving fluidity. In general, it is 1 to 20% by weight, preferably 2 to 16% by weight, more preferably 2 to 15% by weight of the total weight of the solid preparation for internal use.
本発明の内服用固形製剤、内服用固形製剤の吸湿抑制及び／又は流動性改善方法、吸湿抑制及び／又は流動性改善された内服用固形製剤の製造方法、並びに内服用固形製剤の吸湿抑制及び／又は流動性改善剤において、当該製剤は、（Ａ）成分及び（Ｂ）成分以外に、必要に応じてさらなる種々の成分（薬理活性成分や生理活性成分）を含み得るか、またはそれらと組み合わせて使用され得る。このような成分の種類は特に制限されず、例えば、制酸剤、消化剤、整腸剤、健胃剤、止瀉剤、鎮痛鎮痙剤、粘膜修復剤、消泡剤などが例示できる。本発明において好適な成分としては、例えば、次のような成分が挙げられるが、これらの成分に限定されるものではない。なお、これらの成分の配合量は製剤の種類、成分の種類などに応じて適宜選択される。
制酸剤としては、乾燥水酸化アルミニウムゲル、ケイ酸アルミン酸マグネシウム、ケイ酸マグネシウム、合成ケイ酸アルミニウム、ヒドロタルサイト、水酸化マグネシウム、水酸化アルミナマグネシウム、水酸化アルミニウムゲル、水酸化アルミニウム・炭酸水素ナトリウム共沈生成物、水酸化アルミニウム・炭酸マグネシウム混合乾燥ゲル、水酸化アルミニウム・炭酸マグネシウム・炭酸カルシウム共沈生成物、酸化マグネシウム、炭酸水素ナトリウム、炭酸マグネシウム、メタケイ酸アルミン酸マグネシウム、無水リン酸水素カルシウム、リン酸水素カルシウム、烏賊骨、石決明、牡蠣、アミノ酢酸、及びジヒドロキシアルミニウムアミノアセテート等が挙げられる。なかでも制酸剤として、乾燥水酸化アルミニウムゲル、合成ヒドロタルサイト、酸化マグネシウム、水酸化マグネシウム、炭酸水素ナトリウム、炭酸マグネシウム、沈降炭酸カルシウム、メタケイ酸アルミン酸マグネシウム、ジヒドロキシアルミニウムアミノアセテート等が好ましい成分として挙げられる。
消化剤としては、でんぷん消化酵素、たん白消化酵素、脂肪消化酵素、繊維素消化酵素、ウルソデスオキシコール酸、オキシコーラン酸塩類、コール酸、胆汁末（胆汁エキスを含む）、デヒドロコール酸、動物肝（ユウタンを含む）等が挙げられる。なかでも、でんぷん消化酵素、たん白消化酵素、脂肪消化酵素、繊維素消化酵素、ウルソデスオキシコール酸が好ましい。
整腸剤としては、整腸生菌成分、アカメガシワ、アセンヤク、ウバイ、ケツメイシ、ゲンノショウコ等が挙げられる。
Solid preparation for internal use of the present invention, method for suppressing moisture absorption and / or improving fluidity of solid preparation for internal use, method for producing solid preparation for internal use with improved moisture absorption and / or fluidity, and suppressing moisture absorption of solid preparation for internal use and In the fluidity improver, the preparation may contain various components (pharmacologically active components and physiologically active components) as necessary in addition to the components (A) and (B), or a combination thereof. Can be used. The type of such components is not particularly limited, and examples thereof include antacids, digestive agents, intestinal regulating agents, gastric agents, antipruritic agents, analgesic / antispasmodic agents, mucosal repair agents, and antifoaming agents. Examples of suitable components in the present invention include the following components, but are not limited to these components. In addition, the compounding quantity of these components is suitably selected according to the kind of formulation, the kind of component, etc.
As antacids, dry aluminum hydroxide gel, magnesium aluminate silicate, magnesium silicate, synthetic aluminum silicate, hydrotalcite, magnesium hydroxide, magnesium alumina alumina, aluminum hydroxide gel, aluminum hydroxide / carbonic acid Sodium hydrogen coprecipitation product, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitation product, magnesium oxide, sodium hydrogen carbonate, magnesium carbonate, magnesium aluminate metasilicate, anhydrous phosphoric acid Calcium hydrogen, calcium hydrogen phosphate, bandit bone, stone decision, oyster, aminoacetic acid, dihydroxyaluminum aminoacetate and the like. Among them, preferable components such as dry aluminum hydroxide gel, synthetic hydrotalcite, magnesium oxide, magnesium hydroxide, sodium hydrogen carbonate, magnesium carbonate, precipitated calcium carbonate, magnesium aluminate metasilicate, and dihydroxyaluminum aminoacetate are preferred as antacids. As mentioned.
As digestive agents, starch digestive enzymes, protein digestive enzymes, fat digestive enzymes, fibrin digestive enzymes, ursodeoxycholic acid, oxycoranoates, cholic acid, bile powder (including bile extract), dehydrocholic acid, Examples include animal liver (including yutan). Of these, starch digestive enzyme, protein digestive enzyme, fat digestive enzyme, fibrin digestive enzyme, and ursodeoxycholic acid are preferable.
Examples of the intestinal regulating agent include live intestinal fungi components, red-crowned wrinkles, asenyaku, powdery rice, ketsumeishi, and ganosho.
本発明の内服用固形製剤、内服用固形製剤の吸湿抑制及び／又は流動性改善方法、吸湿抑制及び／又は流動性改善された内服用固形製剤の製造方法、並びに内服用固形製剤の吸湿抑制及び／又は流動性改善剤において、当該製剤を調製するにあたり、通常使用される充填剤、増量剤、結合剤、補形剤、付湿剤、崩壊剤、表面活性剤、滑沢剤、徐放化剤などの希釈剤や賦形剤を用いることができる。この他必要に応じて溶解補助剤、緩衝剤、保存剤、可溶化剤、等張化剤、乳化剤、懸濁化剤、分散剤、増粘剤、ゲル剤、硬化剤、吸収剤、粘着剤、弾性剤、可塑剤、吸着剤、香料、着色剤、矯味剤、抗酸化剤、保存剤、保湿剤、遮光剤、光沢剤、帯電防止剤、コーティング剤、矯臭剤、香味剤、芳香剤などを使用することができる。より具体的には、賦形剤として、乳糖、コーンスターチ、Ｄ−マンニトール、Ｄ−ソルビトール、結晶セルロース、エリスリトール、白糖など、結合剤としてヒドロキシプロピルセルロース（ＨＰＣ）、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、メチルセルロース、α化デンプンなど、崩壊剤として、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、架橋化ポリビニルピロリドンなど、滑沢剤としてステアリン酸マグネシウム、タルクなど、香料としては、ｌ−メントール、バニリン、レモン油、ケイヒ油、ハッカ油などのフレーバーや芳香油が挙げられ、吸着剤として合成ケイ酸アルミニウム、軽質無水ケイ酸、多孔性ケイ酸カルシウム、メタケイ酸アルミン酸マグネシウム、ケイ酸アルミン酸マグネシウムなどを配合するのが好ましい。 Solid preparation for internal use of the present invention, method for suppressing moisture absorption and / or improving fluidity of solid preparation for internal use, method for producing solid preparation for internal use with improved moisture absorption and / or fluidity, and suppressing moisture absorption of solid preparation for internal use and In the preparation of the preparation for the flowability improver, ordinarily used fillers, extenders, binders, excipients, moisturizers, disintegrants, surfactants, lubricants, sustained release Diluents and excipients such as agents can be used. Other solubilizers, buffers, preservatives, solubilizers, tonicity agents, emulsifiers, suspending agents, dispersants, thickeners, gels, curing agents, absorbents, adhesives as necessary , Elastic agents, plasticizers, adsorbents, fragrances, colorants, flavoring agents, antioxidants, preservatives, moisturizers, light-shielding agents, brighteners, antistatic agents, coating agents, flavoring agents, flavoring agents, fragrances, etc. Can be used. More specifically, as an excipient, lactose, corn starch, D-mannitol, D-sorbitol, crystalline cellulose, erythritol, sucrose, etc., binders hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose, polyvinylpyrrolidone, methylcellulose, Pregelatinized starch, disintegrating agents such as carmellose calcium, croscarmellose sodium, cross-linked polyvinyl pyrrolidone, lubricants such as magnesium stearate, talc, etc., and flavors such as l-menthol, vanillin, lemon oil, cinnamon oil Flavors such as peppermint oil and aromatic oils, and synthetic aluminum silicate, light anhydrous silicic acid, porous calcium silicate, magnesium metasilicate aluminate, magnesium silicate magnesium Preferably added, and the like.
本発明の内服用固形製剤、内服用固形製剤の吸湿抑制及び／又は流動性改善方法、吸湿抑制及び／又は流動性改善された内服用固形製剤の製造方法、並びに内服用固形製剤の吸湿抑制及び／又は流動性改善剤において、当該内服用固形製剤は、通常の内服用組成物と同様の方法で投与することができ、所望の投与量範囲内において、１日につき、１〜４回程度に分けて、食前、食間、食後、就寝前等に服用することができる。
なお、本明細書中の用語「投与」は、「服用」を包含することを意図して用いられる。
また、本明細書中の用語「内服」は、「経口投与」と互換的に用いられ得る。
本発明の内服用固形製剤の投与量は、その形態、投与方法、投与目的及び当該組成物の投与対象者の年齢、体重、症状によって適宜設定され、一定ではないが、（Ａ）成分の投与量としては、例えば、胃腸薬として服用する場合、通常、成人１日あたり１２０〜６００ｍｇ程度である。また、（Ｂ）成分の投与量としては、例えば、胃腸薬として服用する場合、通常、成人１日あたり３６〜１８０ｍｇ程度である。
本発明の内服用固形製剤、内服用固形製剤の吸湿抑制及び／もしくは流動性改善方法、吸湿抑制及び／もしくは流動性改善された内服用固形製剤の製造方法、及び内服用固形製剤の吸湿抑制及び／もしくは流動性改善剤において、（Ａ）カルニチン又はその塩、及び、（Ｂ）ジメチルポリシロキサン又はその誘導体を含有することから、当該製剤は、特に胃腸薬として有用である。具体的には、もたれ（胃もたれ）、食べ過ぎ（過食）、飲み過ぎ（過飲）、胸やけ、食欲不振（食欲減退）、胃部膨満感（消化不良によるものを含む）、腹部膨満感（消化不良によるものを含む）、はきけ（むかつき、胃のむかつき、二日酔・悪酔のむかつき、嘔気、悪心）、嘔吐、胸つかえ、胃酸過多、胃重、胃弱、胃痛、胃部不快感、消化促進、消化不良、腹痛、さしこみ（疝痛（せんつう）、癲（しゃく））、げっぷ（おくび）、はき下し、くだり腹、下痢（消化不良による下痢及び腹痛を伴う下痢を含む）、食あたり、水あたり、整腸（便通を整える）、軟便、便秘などの用途に用いることができる。
本発明の内服用固形製剤は、例えば、医薬品、医薬部外品、食品、又はこれらの原料〔例えば、医薬製剤、医薬部外品製剤、特定保健用食品、栄養機能食品、老人用食品、特別用途食品、機能性食品、健康補助食品（サプリメント）、食品用製剤（例、製菓錠剤）〕として用いることができる。
Solid preparation for internal use of the present invention, method for suppressing moisture absorption and / or improving fluidity of solid preparation for internal use, method for producing solid preparation for internal use with improved moisture absorption and / or fluidity, and suppressing moisture absorption of solid preparation for internal use and In the fluidity improver, the solid preparation for internal use can be administered in the same manner as the composition for normal internal use, and it is about 1 to 4 times per day within the desired dose range. It can be taken separately before meals, between meals, after meals, before going to bed.
In addition, the term “administration” in the present specification is intended to include “taking”.
In addition, the term “internal use” in the present specification may be used interchangeably with “oral administration”.
The dosage of the solid preparation for internal use of the present invention is appropriately set according to the form, administration method, administration purpose and age, weight, and symptom of the subject of administration of the composition, and although not constant, administration of component (A) As an amount, for example, when taken as a gastrointestinal drug, it is usually about 120 to 600 mg per day for an adult. In addition, the dose of the component (B) is usually about 36 to 180 mg per day for an adult when taken as a gastrointestinal drug, for example.
Solid preparation for internal use of the present invention, method for suppressing moisture absorption and / or improving fluidity of solid preparation for internal use, method for producing solid preparation for internal use having improved moisture absorption and / or fluidity, and suppressing moisture absorption of solid preparation for internal use and Since the fluidity improver contains (A) carnitine or a salt thereof and (B) dimethylpolysiloxane or a derivative thereof, the preparation is particularly useful as a gastrointestinal drug. Specifically, lean (stomach), overeating (overeating), excessive drinking (overdrinking), heartburn, loss of appetite (decreased appetite), stomach fullness (including those caused by indigestion), abdominal fullness (Including those caused by indigestion), rash (upset, upset stomach, upset hangover / nausea, nausea, nausea), vomiting, chest retention, hyperacidity, stomach weight, weakness of stomach, stomach pain, stomach discomfort , Digestion promotion, indigestion, abdominal pain, squeeze (cough, shackles), burp, snagging, belly, diarrhea (including diarrhea due to indigestion and diarrhea with abdominal pain) It can be used for purposes such as per meal, per water, intestinal regulation (to adjust bowel movements), soft stool, and constipation.
The solid preparation for internal use of the present invention is, for example, a pharmaceutical, a quasi-drug, a food, or a raw material thereof (for example, a pharmaceutical preparation, a quasi-drug preparation, a food for specified health use, a nutritional functional food, a food for the elderly, a special food, Use food, functional food, health supplement (supplement), food preparation (eg, confectionery tablet)].
当該本発明の製剤は、（Ａ）成分及び（Ｂ）成分を含有するのであれば特に限定はなく、日本薬局方製剤総則等に記載の公知の方法に基づき製造、製剤化することができる。具体的には、本発明の内服用固形製剤が顆粒である場合、例えば、前記各成分、必要によりその他薬理活性成分や生理活性成分、添加剤を含む原料を、造粒（例えば、押出し造粒、流動層造粒、又は噴霧乾燥式造粒等）、乾燥、及び篩過して製造できる。ここで（Ｂ）成分は、あらかじめ、軽質無水ケイ酸、含水二酸化ケイ素等の多孔性物質等に吸着させたものを用いてもよい。また、顆粒剤は、（Ａ）成分と（Ｂ）成分とを含有する単一の顆粒剤でも、組成の異なる２種以上の顆粒剤を組み合わせても良く、（Ａ）成分を含有する顆粒剤と（Ｂ）成分を含有する顆粒剤とを組み合わせて顆粒剤としてもよい。この顆粒剤を用いて、更に通常の方法により、カプセル剤、又は錠剤を製造できる。 The preparation of the present invention is not particularly limited as long as it contains the component (A) and the component (B), and can be manufactured and formulated based on a known method described in the Japanese Pharmacopoeia Preparation General Rules and the like. Specifically, when the solid preparation for internal use of the present invention is a granule, for example, the above ingredients, if necessary, other pharmacologically active ingredients, physiologically active ingredients, and raw materials containing additives are granulated (for example, extruded granulation). , Fluidized bed granulation, spray drying granulation, etc.), drying, and sieving. Here, the component (B) may be previously adsorbed on a porous substance such as light anhydrous silicic acid or hydrous silicon dioxide. Further, the granule may be a single granule containing the component (A) and the component (B), or a combination of two or more types of granules having different compositions, and the granule containing the component (A) And a granule containing the component (B) may be combined to form a granule. Using these granules, capsules or tablets can be produced by a conventional method.
本発明の内服用固形製剤の剤形としては、粉剤、錠剤〔素錠、糖衣錠、口腔内速崩壊錠、咀嚼可能錠（チュアブル錠）、発泡錠、トローチ剤、フィルムコーティング錠等を含む〕、散剤、顆粒剤、細粒剤、カプセル剤、丸剤、ドライシロップ剤、及び製菓剤〔キャンディー（飴）、グミ剤、ヌガー剤等を含む〕が例示される。特に、錠剤、散剤、顆粒剤、カプセル剤が好ましい。 Examples of the dosage form of the solid preparation for internal use of the present invention include powders, tablets (including plain tablets, dragees, intraoral quick disintegrating tablets, chewable tablets (chewable tablets), effervescent tablets, troches, film-coated tablets, etc.), Examples include powders, granules, fine granules, capsules, pills, dry syrups, and confectionery agents (including candy, gummy agents, nougat agents, etc.). In particular, tablets, powders, granules, and capsules are preferable.
以下で、本発明を実施例をもって説明するが、内服用固形製剤の吸湿抑制及び／又は流動性改善剤として、ジメチルポリシロキサン又はその誘導体の優位の効果を確認するためのものであって、本発明の技術的範囲を限定するものではない。 Hereinafter, the present invention will be described with reference to examples, but it is intended to confirm the advantageous effects of dimethylpolysiloxane or a derivative thereof as a moisture absorption inhibitor and / or fluidity improver for solid preparations for internal use. It is not intended to limit the technical scope of the invention.
製剤例１（粉剤）
表１に従い、塩化カルニチン〔カルニチン塩化物、金剛化学（株）製〕、ジメチルポリシロキサン〔東レ・ダウコーリング（株）製〕、結晶セルロース（セオラスPH-101、旭化成ケミカル）、メタケイ酸アルミン酸マグネシウム〔ノイシリンUFL2、富士化学工業（株）製〕、及びステアリン酸マグネシウム〔太平化学産業（株）製〕を秤量し、混合及び均一化を行い、粉剤を得た。得られた粉剤は、比較試験において試験製剤１〜４（ジメチルポリシロキサン添加量を変えた）として吸湿性及び流動性の評価を行った。
According to Table 1, carnitine chloride [carnitine chloride, manufactured by Kongo Chemical Co., Ltd.], dimethylpolysiloxane [manufactured by Toray Dow Calling Co., Ltd.], crystalline cellulose (Theoras PH-101, Asahi Kasei Chemical), magnesium metasilicate aluminate [Neusilin UFL2, manufactured by Fuji Chemical Industry Co., Ltd.] and magnesium stearate [produced by Taihei Chemical Industry Co., Ltd.] were weighed, mixed and homogenized to obtain a powder. The obtained powder was evaluated for hygroscopicity and fluidity as test preparations 1 to 4 (with different amounts of dimethylpolysiloxane added) in a comparative test.
製剤例２（顆粒剤）
表２に従い、塩化カルニチン（カルニチン塩化物）、ジメチルポリシロキサン、トウモロコシデンプン、ヒドロキシプロピルセルロース、及び軽質無水ケイ酸、を秤量し、混合及び均一化を行い、湿式造粒により、平均粒子径142〜198μmの顆粒剤を得た。得られた、顆粒剤は、比較試験において試験製剤５〜８（ジメチルポリシロキサン添加量を変えた）として吸湿性及び流動性の評価を行った。
According to Table 2, carnitine chloride (carnitine chloride), dimethylpolysiloxane, corn starch, hydroxypropylcellulose, and light anhydrous silicic acid are weighed, mixed and homogenized, and wet granulation is performed to obtain an average particle size of 142 to 198 μm granules were obtained. The obtained granules were evaluated for hygroscopicity and fluidity as
製剤例３（錠剤）
表３に従い、塩化カルニチン（カルニチン塩化物）、ジメチルポリシロキサン、バレイショデンプン、メタケイ酸アルミン酸マグネシウム、及びステアリン酸マグネシウムを秤量し、混合及び均一化を行い、直径９．５ｍｍの臼杵を用いて、常法により混合粉を圧縮して、錠剤を得た。得られた錠剤は、比較試験において試験製剤９〜１２（ジメチルポリシロキサン添加量を変えた）として吸湿性の評価を行った。
According to Table 3, carnitine chloride (carnitine chloride), dimethylpolysiloxane, potato starch, magnesium aluminate metasilicate, and magnesium stearate are weighed, mixed and homogenized, using a mortar with a diameter of 9.5 mm, The mixed powder was compressed by a conventional method to obtain tablets. The obtained tablets were evaluated for hygroscopicity as test preparations 9 to 12 (addition amount of dimethylpolysiloxane was changed) in a comparative test.
製剤例４（カプセル剤）
表４に従い、塩化カルニチン（カルニチン塩化物）、ジメチルポリシロキサン、トウモロコシデンプン、低置換度ヒドロキシプロピルセルロース、及び軽質無水ケイ酸を秤量し、混合及び均一化を行い、湿式造粒により、顆粒剤を得た。得られた顆粒剤を、常法に従い、カプセルに充填した。
According to Table 4, carnitine chloride (carnitine chloride), dimethylpolysiloxane, corn starch, low-substituted hydroxypropylcellulose, and light anhydrous silicic acid are weighed, mixed and homogenized, and granulated by wet granulation. Obtained. The obtained granules were filled into capsules according to a conventional method.
製剤例５（チュアブル錠）
表５に従い、塩化カルニチン（カルニチン塩化物）、ジメチルポリシロキサン、D-マンニトール、結晶セルロース、ケイ酸アルミン酸マグネシウム、及びステアリン酸マグネシウムを秤量し、混合及び均一化を行い、湿式造粒により、顆粒剤を得た。得られた顆粒剤を、直径９．５ｍｍの臼杵を用いて、常法により圧縮して、チュアブル錠を得た。
According to Table 5, carnitine chloride (carnitine chloride), dimethylpolysiloxane, D-mannitol, crystalline cellulose, magnesium aluminate silicate, and magnesium stearate are weighed, mixed and homogenized, and granulated by wet granulation. An agent was obtained. The obtained granule was compressed by a conventional method using a mortar with a diameter of 9.5 mm to obtain a chewable tablet.
比較試験１
製剤例１で調製した粉剤を使い、ジメチルポリシロキサンの添加量による、カルニチン塩化物を含有する内服用固形製剤の吸湿性及び流動性の改善評価を行った。試験製剤中の成分の配合比は表１の通りであり、吸湿性の評価は、試験粉体を、恒湿デシケータで保存（75%RH, 25℃）し、2、40、50時間後に試験粉体を取り出し、その際の赤外水分値を測定（赤外水分計 FD-720、ケット科学研究所製）することによって行い、流動性の評価は、試験粉体を用いて、恒湿デシケータで24時間保存（75%RH, 25℃）した後、安息角を測定することによって、行った。
図１及び表６に示すようにジメチルポリシロキサンの配合量を増すことで優位に、製剤中の水分含有量の経時的な増加が抑えられ、ジメチルポリシロキサンの配合により、カルニチン塩化物を含有する内服用固形製剤の吸湿を抑えられることが示された。
保存（75%RH, 25℃）後の試験製剤の水分含有量（%）− 保存開始時の試験製剤の水分含有量（%）
流動性については、表７に示すように、ジメチルポリシロキサンを配合することで、初期の安息角は大きくなるが、安息角の経時的な変化は小さくなり、流動性の変化を抑制することがわかった。すなわち、カルニチン塩化物とジメチルポリシロキサンを含有する粉剤とすれば、長時間にわたり粉剤の流動性の変化が抑制される（流動性の変化が小さい）ため、粉剤を容器などに充填する際の条件を、製造工程の途中や製造ロットごとに変更する必要がなく、製造効率がよくなることが示唆される。また、カルニチン塩化物とジメチルポリシロキサンを含有する粉剤を用いて錠剤や顆粒剤等を製造する場合にも、錠剤や顆粒剤等の製造条件を、製造工程の途中や製造ロットごとに変更する必要がなく、製造効率がよくなることが示唆される。
＝保存後の試験製剤の安息角 − 保存開始時の試験製剤の安息角
Comparative test 1
Using the powder prepared in Formulation Example 1, the improvement in hygroscopicity and fluidity of a solid preparation for internal use containing carnitine chloride was evaluated by the amount of dimethylpolysiloxane added. The composition ratio of the components in the test preparation is as shown in Table 1. Hygroscopicity is evaluated by storing the test powder in a constant humidity desiccator (75% RH, 25 ° C) and testing after 2, 40, and 50 hours. Take out the powder and measure the infrared moisture value at that time (infrared moisture meter FD-720, manufactured by Kett Science Laboratory). The fluidity is evaluated using a test powder and a constant humidity desiccator. And then stored for 24 hours (75% RH, 25 ° C.) and then by measuring the angle of repose.
As shown in FIG. 1 and Table 6, an increase in the amount of water content in the preparation is advantageously suppressed by increasing the amount of dimethylpolysiloxane, and carnitine chloride is contained by the addition of dimethylpolysiloxane. It was shown that moisture absorption of the solid preparation for internal use can be suppressed.
Water content of test preparation after storage (75% RH, 25 ° C) (%)-Water content of test preparation at start of storage (%)
As for the fluidity, as shown in Table 7, by adding dimethylpolysiloxane, the initial angle of repose increases, but the change in angle of repose over time decreases, suppressing the change in fluidity. all right. That is, if a powder containing carnitine chloride and dimethylpolysiloxane is used, the change in the fluidity of the powder is suppressed for a long time (the change in fluidity is small). Is not required to be changed during the manufacturing process or for each manufacturing lot, which suggests that manufacturing efficiency is improved. In addition, when manufacturing tablets and granules using powder containing carnitine chloride and dimethylpolysiloxane, it is necessary to change the manufacturing conditions for tablets and granules in the middle of the manufacturing process and for each manufacturing lot. This suggests that the production efficiency is improved.
= Angle of repose of test preparation after storage-Angle of repose of test preparation at the start of storage
比較試験２
製剤例２で調製した顆粒剤を使い、試験製剤５〜８においてジメチルポリシロキサンの添加量による、カルニチン塩化物を含有する内服用固形製剤の吸湿性及び流動性の改善評価を行った。試験製剤中の成分の配合比は表２の通りであり、吸湿性の評価及び流動性の評価は、比較試験１と同様に行った。
評価結果を、図２及び表８〜９に示した。粉剤の場合と同様に、顆粒剤の場合にも、ジメチルポリシロキサンの配合量を増すことで優位に、製剤中の水分含有量及び安息角の経時的な増加が抑えられ、ジメチルポリシロキサンの配合により、カルニチン塩化物を含有する内服用固形製剤の吸湿性及び流動性の変化を抑えられることが示された。
Using the granule prepared in Formulation Example 2, the hygroscopicity and fluidity improvement evaluation of the solid preparation for internal use containing carnitine chloride was performed according to the addition amount of dimethylpolysiloxane in
The evaluation results are shown in FIG. 2 and Tables 8-9. As in the case of powders, in the case of granules, the increase in the water content and angle of repose of the formulation over time can be suppressed by increasing the amount of dimethylpolysiloxane. Thus, it was shown that changes in hygroscopicity and fluidity of a solid preparation for internal use containing carnitine chloride can be suppressed.
比較試験３
製剤例３で調製した錠剤を使い、試験製剤９〜１２においてジメチルポリシロキサンの添加量による、カルニチン塩化物を含有する内服用固形製剤について、吸湿性改善の評価を行った。試験製剤中の成分の配合比は表３の通りであり、吸湿性の評価は比較試験１と同様に行った。
評価結果を、図３及び表１０に示した。粉剤の場合と同様に、錠剤の場合にも、ジメチルポリシロキサンの配合量を増すことで優位に、製剤中の水分含有量の経時的な増加が抑えられ、ジメチルポリシロキサンの配合により、カルニチン塩化物を含有する内服用固形製剤の吸湿が抑えられることが示された。
Using the tablets prepared in Formulation Example 3, the hygroscopic improvement was evaluated for the solid preparations for internal use containing carnitine chloride according to the addition amount of dimethylpolysiloxane in Test preparations 9 to 12. The compounding ratios of the components in the test preparation are as shown in Table 3, and the hygroscopic evaluation was performed in the same manner as in Comparative Test 1.
The evaluation results are shown in FIG. As in the case of powders, in the case of tablets, increasing the amount of dimethylpolysiloxane is advantageous, and the increase in moisture content over time can be suppressed. It was shown that the moisture absorption of the solid preparation for internal use containing the product can be suppressed.
（Ａ）カルニチン又はその塩から選択される少なくとも一つの化合物と、（Ｂ）ジメチルポリシロキサン又はその誘導体から選択される少なくとも一つの化合物を含有する内服用固形製剤は、新規な配合の内服用固形製剤を提供し、しかも、該内服用固形製剤は、吸湿性及び流動性が優れており、内服用固形製剤の保存における経時安定性を高めることから、内服用固形製剤分野の技術的多様性を高めるものである。 A solid preparation for internal use containing (A) at least one compound selected from carnitine or a salt thereof, and (B) at least one compound selected from dimethylpolysiloxane or a derivative thereof, In addition, the solid preparation for internal use has excellent hygroscopicity and fluidity, and improves the stability over time in storage of the solid preparation for internal use. It is something to enhance.
Claims (5)
（Ｂ）ジメチルポリシロキサンと、
（Ｃ）Ｄ−マンニトール、結晶セルロース、ヒドロキシプロピルセルロース（ＨＰＣ）、α化デンプン、ステアリン酸マグネシウム、軽質無水ケイ酸から選択される少なくとも一種とを含有し、
（Ａ）カルニチン又はその塩から選択される少なくとも一つの化合物の含有量が、固形製剤全重量の９．７〜４１．５重量％であり、
（Ｂ）ジメチルポリシロキサンの含有量が、（Ａ）カルニチン又はその塩から選択される少なくとも一つの化合物の１００重量部に対し、３０〜１５０重量部である
内服用固形製剤。 (A) at least one compound selected from carnitine or a salt thereof;
(B) a dimethylpolysiloxane,
(C) at least one selected from D-mannitol, crystalline cellulose, hydroxypropyl cellulose (HPC), pregelatinized starch, magnesium stearate, and light anhydrous silicic acid ,
(A) content of carnitine or at least one compound selected from a salt thereof, Ri 9.7 to 41.5 wt% der of the solid preparation total weight,
The solid preparation for internal use , wherein the content of (B) dimethylpolysiloxane is 30 to 150 parts by weight with respect to 100 parts by weight of at least one compound selected from (A) carnitine or a salt thereof .
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