JPWO2007135774A1 - Herbal medicine-containing oral solution composition - Google Patents

Herbal medicine-containing oral solution composition Download PDF

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JPWO2007135774A1
JPWO2007135774A1 JP2008516559A JP2008516559A JPWO2007135774A1 JP WO2007135774 A1 JPWO2007135774 A1 JP WO2007135774A1 JP 2008516559 A JP2008516559 A JP 2008516559A JP 2008516559 A JP2008516559 A JP 2008516559A JP WO2007135774 A1 JPWO2007135774 A1 JP WO2007135774A1
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俊樹 薄井
俊樹 薄井
泰弘 新川
泰弘 新川
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    • A61K36/18—Magnoliophyta (angiosperms)
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    • A61K36/65—Paeoniaceae (Peony family), e.g. Chinese peony
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    • A61K36/54—Lauraceae (Laurel family), e.g. cinnamon or sassafras
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    • A61K36/72—Rhamnaceae (Buckthorn family), e.g. buckthorn, chewstick or umbrella-tree
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Abstract

低温条件下で長期間安定な生薬配合経口液剤組成物の提供。次の成分（Ａ）〜（Ｆ）：（Ａ）人参、ショウキョウ、タイソウ、シャクヤク、トウキ及びケイヒから選ばれる１種又は２種以上の生薬（Ｂ）ショ糖脂肪酸エステル（Ｃ）モノグリセリン脂肪酸エステル（Ｄ）グリチルリチン酸又はその塩（Ｅ）ポリオキシエチレン硬化ヒマシ油（Ｆ）ポリビニルピロリドンを含有することを特徴とする経口液剤組成物。Providing an oral liquid composition containing a herbal medicine that is stable for a long time under low temperature conditions. The following components (A) to (F): (A) one or more herbal medicines selected from carrots, ginger, peony, peony, ginger, and cinnamon (B) sucrose fatty acid ester (C) monoglycerin fatty acid An oral liquid composition comprising ester (D) glycyrrhizic acid or a salt thereof (E) polyoxyethylene hydrogenated castor oil (F) polyvinylpyrrolidone.

Description

本発明は、低温条件下における安定性が良好な生薬配合経口液剤組成物に関する。   The present invention relates to a herbal medicine-containing oral solution composition having good stability under low temperature conditions.

人参、シャクヤク等の生薬は、滋養強壮等の作用を有することから、例えばドリンク剤などとして広く用いられている。ところが、生薬の中には水に対する溶解性が低い成分も多く含まれていることから、沈殿が生じる等の問題がある。かかる問題を解決するため、非イオン性界面活性剤に代表される可溶化剤を配合する技術が報告されている。例えば、特許文献１には、ペオニフロリン含有液体組成物では、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンポリオキシプロピレングリコール、ポリエチレングリコール脂肪酸エステルを配合すると長期間安定になることが記載されている。特許文献２には、ジンセノサイド類を可溶化するには、ポリグリセリン脂肪酸エステル、ポリオキシエチレン系非イオン性界面活性剤及び油成分の組み合わせがよいことが記載されている。特許文献３には、生薬抽出物に、ポリグリセリン脂肪酸エステル、ポリオキシエチレン系非イオン性界面活性剤及び油成分を配合し、ポリオキシエチレン系非イオン性界面活性剤の配合量を、ポリグリセリン脂肪酸エステル１質量部に対して６分の１〜１質量部とした可溶化液体組成物が記載されている。また、特許文献４には、生薬エキスに、ポリオキシエチレン硬化ヒマシ油とポリオキシエチレンポリオキシプロピレン縮合物を配合することが記載されている。
特開２０００−２４７８９０号公報 特開２００２−１９３８２５号公報 特開２００２−１２８７０３号公報 特公平５−９４０８号公報 Herbal medicines such as carrots and peony are widely used as, for example, drinks because they have effects such as nutritional tonic. However, since herbal medicine contains many components with low solubility in water, there are problems such as precipitation. In order to solve such a problem, a technique for blending a solubilizer represented by a nonionic surfactant has been reported. For example, Patent Document 1 describes that a paeoniflorin-containing liquid composition is stable for a long period when polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, and polyethylene glycol fatty acid ester are blended. Patent Document 2 describes that in order to solubilize ginsenosides, a combination of a polyglycerin fatty acid ester, a polyoxyethylene nonionic surfactant and an oil component is good. In Patent Document 3, a polyglycerin fatty acid ester, a polyoxyethylene nonionic surfactant, and an oil component are blended into a herbal extract, and the blending amount of the polyoxyethylene nonionic surfactant is changed to polyglycerin. A solubilized liquid composition having 1 to 1 part by mass of 1/6 to 1 part by mass of fatty acid ester is described. Patent Document 4 describes blending polyoxyethylene hydrogenated castor oil and a polyoxyethylene polyoxypropylene condensate with a crude drug extract.
JP 2000-247890 A JP 2002-193825 A JP 2002-128703 A Japanese Patent Publication No. 5-9408

しかしながら、生薬成分配合液剤の保存安定性は、前記特許文献１及び２のように、配合される生薬成分によっても大きく相違し、特に複数の生薬成分を配合した経口液剤の安定化は困難である。また、冬期や寒冷地の流通過程においては、５℃もの低温になることもあることから、低温条件下で長期間保存した場合でも沈殿や白濁が生じない安定な経口液剤の開発が望まれていた。
従って、本発明は、低温条件下における長期安定性が良好な生薬配合経口液剤組成物を提供することにある。However, the storage stability of the crude drug component-blending liquid is greatly different depending on the blended herbal components as in Patent Documents 1 and 2, and it is particularly difficult to stabilize an oral liquid containing a plurality of herbal components. . In the winter and cold districts, the temperature may be as low as 5 ° C. Therefore, the development of a stable oral solution that does not cause precipitation or cloudiness even when stored for a long time under low temperature conditions is desired. It was.
Accordingly, it is an object of the present invention to provide an herbal medicine-containing oral solution composition having good long-term stability under low temperature conditions.

そこで本発明者は、生薬成分を配合した液剤の安定性について検討してきたところ、ショ糖脂肪酸エステルと、モノグリセリン脂肪酸エステルと、グリチルリチン酸又はその塩を組み合せて配合すれば、高温条件下だけでなく低温条件下でも約１ヶ月沈殿を生じず、安定な経口液剤が得られることを見出した。さらに検討を続けた結果、上記ショ糖脂肪酸エステルと、モノグリセリン脂肪酸エステルと、グリチルリチン酸又はその塩に加えて、ポリオキシエチレン硬化ヒマシ油と、ポリビニルピロリドンとを組み合せて配合すれば、低温条件で２ヶ月以上もの長期間沈殿や白濁を生じず、特に、沈殿の生じやすい、冬期や寒冷地での流通において有用な生薬成分配合液剤が得られることを見出し、本発明を完成した。   Therefore, the present inventor has examined the stability of a liquid preparation containing a crude drug component. If a combination of a sucrose fatty acid ester, a monoglycerin fatty acid ester, and glycyrrhizic acid or a salt thereof is combined, only under high temperature conditions. It was also found that a stable oral solution can be obtained without precipitation for about one month even under low temperature conditions. As a result of further investigation, in addition to the above sucrose fatty acid ester, monoglycerin fatty acid ester, glycyrrhizic acid or a salt thereof, a combination of polyoxyethylene hydrogenated castor oil and polyvinylpyrrolidone can be combined at low temperature conditions. The present invention was completed by finding that a crude drug component-containing liquid preparation that does not cause precipitation or cloudiness for a long period of 2 months or longer and that is particularly prone to precipitation and that is useful for distribution in winter or cold regions can be obtained.

すなわち、本発明は、次の成分（Ａ）〜（Ｆ）：
（Ａ）人参、ショウキョウ、タイソウ、シャクヤク、トウキ、及びケイヒから選ばれる１種又は２種以上の生薬
（Ｂ）ショ糖脂肪酸エステル
（Ｃ）モノグリセリン脂肪酸エステル
（Ｄ）グリチルリチン酸又はその塩
（Ｅ）ポリオキシエチレン硬化ヒマシ油
（Ｆ）ポリビニルピロリドン
を含有することを特徴とする経口液剤組成物を提供するものである。That is, the present invention includes the following components (A) to (F):
(A) One or more herbal medicines selected from ginseng, ginger, peony, peony, toki, and keihi (B) sucrose fatty acid ester (C) monoglycerin fatty acid ester (D) glycyrrhizic acid or a salt thereof ( E) An oral liquid composition comprising polyoxyethylene hydrogenated castor oil (F) polyvinylpyrrolidone is provided.

本発明の経口液剤組成物は、低温条件において長期間沈殿及び白濁を生じることなく安定である。従って、本発明の経口液剤組成物は、冬期や寒冷地において安定に流通させることができる。   The oral liquid composition of the present invention is stable without causing long-term precipitation and cloudiness at low temperature conditions. Therefore, the oral liquid composition of the present invention can be distributed stably in winter and cold regions.

本発明において使用される生薬成分（Ａ）は、人参、ショウキョウ、タイソウ、シャクヤク、トウキ、及びケイヒから選ばれる１種又は２種以上である。ここで人参としては、ウコギ科のオタネニンジンの根の抽出物が用いられる。ショウキョウとしては、ショウガ科のショウガの根茎の抽出物が用いられる。タイソウとしては、クロウメモドキ科のナツメの果実の抽出物が用いられる。シャクヤクとしては、ボタン科のシャクヤクの根の抽出物が用いられる。トウキとしては、セリ科のトウキの根の抽出物が用いられる。ケイヒとしては、クスノキ科のシナモンカシアの樹皮の抽出物が用いられる。抽出物の形態は特に限定されず、例えば乾燥エキス、流エキス、軟エキスなどが挙げられるが、本発明においては流エキス、又は軟エキスを用いるのが好ましい。なお、これらの抽出物を得るための抽出溶媒としては、水、エタノール等が挙げられる。   The herbal medicine component (A) used in the present invention is one or more selected from carrots, ginger, ginseng, peony, ginger, and keihi. Here, as a carrot, an extract of the root of ginseng of the family Araceae is used. As the ginger, a ginger rhizome extract is used. As the Taisou, an extract of jujube fruit belonging to the family Aceraceae is used. As the peony, an extract of peony root of the button family is used. As the touki, an extract of the roots of the ciraceae is used. An extract of the bark of the cinnamon cassia of the camphor family is used as Keihi. The form of the extract is not particularly limited, and examples thereof include a dry extract, a stream extract, and a soft extract. In the present invention, it is preferable to use a stream extract or a soft extract. In addition, water, ethanol, etc. are mentioned as an extraction solvent for obtaining these extracts.

これらの生薬成分（Ａ）は、本発明の経口液剤組成物中に１種又は２種以上を配合することができるが、人参を配合し、これに必要に応じて他の前記生薬成分を配合するのが好ましく、さらには人参及びショウキョウを配合し、これに必要に応じてタイソウ、シャクヤク、トウキ及びケイヒから選ばれる１種又は２種以上を配合するのが好ましい。   These herbal medicine components (A) can be blended in the oral liquid composition of the present invention, or one or more thereof, but carrots are blended, and other herbal medicine components are blended as necessary. It is preferable to add ginseng and ginger, and if necessary, one or more selected from tiso, peony, toki and keihi are preferably added.

これらの生薬成分（Ａ）の原生薬換算値としての合計の含有量は、特に制限されるものではないが、薬理効果の点から、本発明の経口液剤組成物中の５〜２５質量％、さらに１０〜２５質量％、特に１５〜２５質量％であるのが好ましい。   The total content of these crude drug ingredients (A) as a raw drug equivalent value is not particularly limited, but from the viewpoint of pharmacological effects, 5 to 25% by mass in the oral liquid composition of the present invention, Furthermore, it is preferable that it is 10-25 mass%, especially 15-25 mass%.

本発明において使用されるショ糖脂肪酸エステル（Ｂ）としては、ショ糖Ｃ14−Ｃ18脂肪酸エステルが好ましい。ショ糖脂肪酸エステル（Ｂ）の市販品としては、ＤＫエステルＳＳ（第一工業製）等が挙げられる。本発明の経口液剤組成物中における生薬成分（Ａ）とショ糖脂肪酸エステル（Ｂ）の含有量の相対質量比率は、特に制限されるものではないが、生薬成分の沈殿発生防止の点から、本発明の経口液剤組成物中における生薬成分（Ａ）の含有量（原生薬換算値）を１とした場合に、ショ糖脂肪酸エステル（Ｂ）の含有量を０．００００４〜０．０２の範囲内とすることが好ましい。また、ショ糖脂肪酸エステル（Ｂ）の含有量は、特に限定されるものではないが、生薬成分の沈殿発生防止の点から、本発明の経口液剤組成物中の０．００１〜０．１質量％、さらに０．００５〜０．０４質量％、特に０．０１〜０．０２質量％であるのが好ましい。The sucrose fatty acid ester used in the present invention (B), sucrose C 14 -C 18 fatty acid esters are preferred. As a commercial item of sucrose fatty acid ester (B), DK ester SS (made by Dai-ichi Kogyo) etc. are mentioned. The relative mass ratio of the content of the crude drug component (A) and the sucrose fatty acid ester (B) in the oral liquid composition of the present invention is not particularly limited, but from the viewpoint of preventing precipitation of the crude drug component, The content of the sucrose fatty acid ester (B) is in the range of 0.00004 to 0.02 when the content of the crude drug component (A) in the oral liquid composition of the present invention is 1 (the value of the crude drug). It is preferable to be inside. The content of the sucrose fatty acid ester (B) is not particularly limited, but is 0.001 to 0.1 mass in the oral liquid composition of the present invention from the viewpoint of preventing the precipitation of the crude drug component. %, More preferably 0.005 to 0.04% by mass, and particularly preferably 0.01 to 0.02% by mass.

本発明において使用されるモノグリセリン脂肪酸エステル（Ｃ）としては、モノグリセリンＣ14−Ｃ18脂肪酸エステルが好ましい。モノグリセリン脂肪酸エステル（Ｃ）の市販品としては、ポエムＭ−１００（理研ビタミン製）等が挙げられる。本発明の経口液剤組成物における生薬成分（Ａ）とモノグリセリン脂肪酸エステル（Ｃ）の含有量の相対質量比率は、特に制限されるものではないが、生薬成分の沈殿発生防止の点から、本発明の経口液剤組成物中における生薬成分（Ａ）の含有量（原生薬換算値）を１とした場合に、モノグリセリン脂肪酸エステル（Ｃ）の含有量を０．００００４〜０．０２の範囲内とすることが好ましい。また、モノグリセリン脂肪酸エステル（Ｃ）の含有量は、特に制限されるものではないが、生薬成分の沈殿発生防止の点から、本発明経口液剤組成物中の０．００１〜０．１質量％、さらに０．００５〜０．０４質量％、特に０．０１〜０．０２質量％であるのが好ましい。As the monoglycerin fatty acid ester (C) used in the present invention, monoglycerin C 14 -C 18 fatty acid ester is preferable. Examples of commercially available monoglycerin fatty acid ester (C) include Poem M-100 (manufactured by Riken Vitamin). The relative mass ratio of the content of the crude drug component (A) and the monoglycerin fatty acid ester (C) in the oral liquid composition of the present invention is not particularly limited, but from the viewpoint of preventing precipitation of the crude drug component, The content of monoglycerin fatty acid ester (C) is within the range of 0.00004 to 0.02, where the content of the crude drug component (A) in the oral liquid composition of the invention is 1 It is preferable that The content of the monoglycerin fatty acid ester (C) is not particularly limited, but is 0.001 to 0.1% by mass in the oral liquid composition of the present invention from the viewpoint of preventing precipitation of the crude drug component. Further, 0.005 to 0.04% by mass, particularly 0.01 to 0.02% by mass is preferable.

本発明において使用されるグリチルリチン酸又はその塩（Ｄ）には、グリチルリチン酸そのもののほか、その薬学的に許容される塩が含まれ、塩としては、例えば、アルカリ金属塩、アルカリ土類金属塩、アンモニウム塩等が挙げられる。グリチルリチン酸又はその塩（Ｄ）としては、例えばグリチルリチン酸二カリウム、グリチルリチン酸モノアンモニウム、グリチルリチン酸二ナトリウム、グリチルリチン酸三ナトリウムなどが例示される。本発明においては、沈殿防止効果の観点からグリチルリチン酸二カリウムが好ましい。グリチルリチン酸又はその塩（Ｄ）の市販品としては、グリチルリチン酸二カリウム（アルプス薬品製）等が挙げられる。本発明の経口液剤組成物における生薬成分（Ａ）とグリチルリチン酸又はその塩（Ｄ）の含有量の相対質量比率は、特に制限されるものではないが、生薬成分の沈殿発生防止の点から、本発明の経口液剤組成物中における生薬成分（Ａ）の含有量（原生薬換算値）を１とした場合に、グリチルリチン酸又はその塩（Ｄ）の含有量を０．００００４〜０．０２の範囲内とすることが好ましい。また、グリチルリチン酸又はその塩（Ｄ）の含有量は、特に制限されるものではないが、生薬成分の沈殿発生防止の点から、本発明の経口液剤組成物中の０．００１〜０．１質量％、さらに０．００５〜０．０４質量％、特に０．０１〜０．０２質量％であるのが好ましい。   Glycyrrhizic acid or a salt thereof (D) used in the present invention includes pharmaceutically acceptable salts in addition to glycyrrhizic acid itself. Examples of the salts include alkali metal salts and alkaline earth metal salts. And ammonium salts. Examples of glycyrrhizic acid or its salt (D) include dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, disodium glycyrrhizinate, trisodium glycyrrhizinate and the like. In the present invention, dipotassium glycyrrhizinate is preferable from the viewpoint of the precipitation preventing effect. Examples of commercially available products of glycyrrhizic acid or its salt (D) include dipotassium glycyrrhizinate (manufactured by Alps Chemicals). The relative mass ratio of the content of the herbal component (A) and the glycyrrhizic acid or its salt (D) in the oral liquid composition of the present invention is not particularly limited, but from the viewpoint of preventing precipitation of the herbal component, The content of glycyrrhizic acid or a salt thereof (D) is 0.00004 to 0.02 when the content of the crude drug component (A) in the oral liquid composition of the present invention is defined as 1 It is preferable to be within the range. The content of glycyrrhizic acid or a salt thereof (D) is not particularly limited, but is 0.001 to 0.1 in the oral liquid composition of the present invention from the viewpoint of preventing precipitation of herbal components. It is preferable that it is mass%, 0.005-0.04 mass%, especially 0.01-0.02 mass%.

本発明において使用されるポリオキシエチレン硬化ヒマシ油（Ｅ）としては、例えばポリオキシエチレン平均付加モル数が５〜１２０の硬化ヒマシ油が挙げられ、特にポリオキシエチレン平均付加モル数が２０〜８０の硬化ヒマシ油が好ましい。ポリオキシエチレン硬化ヒマシ油の市販品としては、ＨＣＯ−６０（日本サーファクタント製）、エマレックスＨＣ−６０（日本エマルジョン製）等が挙げられる。本発明の経口液剤組成物における生薬成分（Ａ）とポリオキシエチレン硬化ヒマシ油（Ｅ）の含有量の相対質量比率は、特に制限されるものではないが、生薬成分の沈殿発生防止の点から、本発明の経口液剤組成物中における生薬成分（Ａ）の含有量（原生薬換算値）を１とした場合に、ポリオキシエチレン硬化ヒマシ油（Ｅ）の含有量を０．００００４〜０．２の範囲内とすることが好ましい。また、ポリオキシエチレン硬化ヒマシ油（Ｅ）の含有量は、特に制限されるものではないが、生薬成分の沈殿発生防止の点から、本発明経口液剤組成物中の０．００１〜１質量％、さらに０．００５〜０．５質量％、特に０．０１〜０．１質量％であるのが好ましい。   Examples of the polyoxyethylene hydrogenated castor oil (E) used in the present invention include hydrogenated castor oil having a polyoxyethylene average addition mole number of 5 to 120, and particularly a polyoxyethylene average addition mole number of 20 to 80. Of hydrogenated castor oil is preferred. As a commercial item of polyoxyethylene hydrogenated castor oil, HCO-60 (manufactured by Nippon Surfactant), Emarex HC-60 (manufactured by Nippon Emulsion) and the like can be mentioned. The relative mass ratio of the content of the crude drug component (A) and the polyoxyethylene hydrogenated castor oil (E) in the oral liquid composition of the present invention is not particularly limited, but from the viewpoint of preventing precipitation of the crude drug component. When the content of the crude drug component (A) in the oral liquid composition of the present invention is defined as 1, the content of the polyoxyethylene hydrogenated castor oil (E) is 0.00004-0. A range of 2 is preferable. The content of the polyoxyethylene hydrogenated castor oil (E) is not particularly limited, but is 0.001 to 1% by mass in the oral liquid composition of the present invention from the viewpoint of preventing precipitation of the crude drug component. Further, 0.005 to 0.5 mass%, particularly 0.01 to 0.1 mass% is preferable.

本発明に用いられるポリビニルピロリドン（Ｆ）としては、平均分子量１０，０００〜２，０００，０００のポリビニルピロリドンが挙げられ、特に平均分子量２０，０００〜５０，０００のポリビニルピロリドンが好ましい。ポリビニルピロリドンの市販品としては、コリドン２５（ＢＡＳＦジャパン製）、アイフタクトＫ−３０（第一工業製薬製）等が挙げられる。本発明の経口液剤組成物における生薬成分（Ａ）とポリビニルピロリドン（Ｆ）の含有量の相対質量比率は、特に制限されるものではないが、白濁発生防止の点から、本発明の経口液剤組成物中における生薬成分（Ａ）の含有量（原生薬換算値）を１とした場合に、ポリビニルピロリドン（Ｆ）の含有量を０．０００４〜０．４の範囲内とすることが好ましい。また、ポリビニルピロリドン（Ｆ）の含有量は、特に制限されるものではないが、白濁発生防止の点から、本発明経口液剤組成物中に０．０１〜２質量％、さらに０．０５〜１質量％、特に０．１〜０．５質量％であるのが好ましい。   Examples of the polyvinyl pyrrolidone (F) used in the present invention include polyvinyl pyrrolidone having an average molecular weight of 10,000 to 2,000,000, and polyvinyl pyrrolidone having an average molecular weight of 20,000 to 50,000 is particularly preferable. Examples of commercially available products of polyvinyl pyrrolidone include Kollidon 25 (manufactured by BASF Japan) and Eye Fact K-30 (manufactured by Daiichi Kogyo Seiyaku). The relative mass ratio of the content of the crude drug component (A) and the polyvinylpyrrolidone (F) in the oral liquid composition of the present invention is not particularly limited, but from the viewpoint of preventing the occurrence of white turbidity, the oral liquid composition of the present invention. When the content of the crude drug component (A) in the product (raw drug substance equivalent value) is 1, the content of polyvinyl pyrrolidone (F) is preferably within the range of 0.0004 to 0.4. The content of polyvinyl pyrrolidone (F) is not particularly limited, but is 0.01 to 2% by mass, and further 0.05 to 1 in the oral liquid composition of the present invention from the viewpoint of preventing clouding. It is preferable that it is mass%, especially 0.1-0.5 mass%.

本発明の経口液剤組成物においては、生薬成分（Ａ）に、ショ糖脂肪酸エステル（Ｂ）、モノグリセリン脂肪酸エステル（Ｃ）、及びグリチルリチン酸又はその塩（Ｄ）だけでなく、さらにポリオキシエチレン硬化ヒマシ油（Ｅ）、及びポリビニルピロリドン（Ｆ）を組み合せて配合することにより、低温条件下での長期保存安定化効果が得られるものである。本発明経口液剤組成物における上記各成分の含有量の相対質量比率は、特に制限されるものではないが、生薬成分の沈殿発生防止、及び白濁発生防止の点から、本発明経口液剤組成物中における生薬成分（Ａ）の含有量（原生薬換算値）を１とした場合に、ショ糖脂肪酸エステル（Ｂ）、モノグリセリン脂肪酸エステル（Ｃ）、及びグリチルリチン酸類又はその塩（Ｄ）の含有量をそれぞれ０．００００４〜０．０２、ポリオキシエチレン硬化ヒマシ油（Ｅ）の含有量を０．００００４〜０．２、ポリビニルピロリドン（Ｆ）の含有量を０．０００４〜０．４の範囲内とすることが好ましい。   In the oral liquid composition of the present invention, not only the crude drug component (A), but also sucrose fatty acid ester (B), monoglycerin fatty acid ester (C), and glycyrrhizic acid or a salt thereof (D), as well as polyoxyethylene By blending hydrogenated castor oil (E) and polyvinylpyrrolidone (F) in combination, a long-term storage stabilization effect under low temperature conditions can be obtained. The relative mass ratio of the content of each component in the oral liquid composition of the present invention is not particularly limited, but from the viewpoint of preventing precipitation of crude drug components and preventing clouding, When the content of the herbal medicine component (A) in the above (concentration value of raw drug) is 1, the content of sucrose fatty acid ester (B), monoglycerin fatty acid ester (C), and glycyrrhizic acid or its salt (D) In the range of 0.00004 to 0.02, the content of polyoxyethylene hydrogenated castor oil (E) is 0.00004 to 0.2, and the content of polyvinylpyrrolidone (F) is in the range of 0.0004 to 0.4. It is preferable that

本発明の経口液剤組成物には、さらに他の薬効成分、甘味剤、ｐＨ調整剤、抗酸化剤、着色剤、香料、矯味剤、保存料、水などを配合することができる。ここで、他の薬効成分としては、アロエ、ウイキョウ、ウコン、ウヤク、エンゴサク、エイジツ、オウギ、オウセイ、オンジ、ガラナ、クコシ、ジオウ、トチュウ、アマロゲンチン、オウゴン、オウバク、オウレン、ガジュツ、カスカラサグラダ、カッコウ、カスカリラノキ、カノコ草、カロウコン、キキョウ、キジツ、キョウニン、キハダ、クコ、クジン、ケイガイ、ケツメイシ、ケンゴシ、ゲンチアナ、ゲンノショウコ、コウジン、コウブシ、コウボク、ゴオウ、ゴシツ、ゴシュユ、ゴミシ、コロンボ、コンズランゴ、サイコ、サンシシ、サフラン、サンショウ、サンズコン、ジオウ、シコン、ジシュユ、シソシ、シャゼン（オオバコ）、ジャ香、ショウマ、セイヒ、セキショウコン、セネガ、センキュウ、センコツ、センタウリウム草、センブリ、センボウ、センソ、センナ、ソウジュツ、ソウハクヒ、ソヨウ、ダイオウ、大蒜、チモ、チレッタ草、チンピ、トウヒ、トウニン、トコン、ニガキ、ビャクシャク、ビャクジュツ、ベラドンナコン、ヘノポジ油、ヤクチ、ユウタン、ヨモギ、ニガヨモギ、苦味チンキ、ホップ、ホミカ、ボウイ、マオウ、モクツウ、モッコウ、ヨクイニン、リュウタン、リンドウ、ルソンカ、レンギョウ、ロクジョウ、及び、ローヤルゼリー等が挙げられる。
甘味剤としては、ショ糖、乳糖、果糖、ブドウ糖、ハチミツ、ソルビトール、マルチトール、エリスリトール、キシリトール、トレハロース、サッカリン及びその塩、アスパルテーム、アセスルファムＫ、ステビア抽出物等が挙げられる。
ｐＨ調整剤としては、ｐＨを４〜７、特に５〜６に調整できるものが挙げられる。
抗酸化剤としては、例えば、アスコルビン酸及びその塩、エリソルビン酸及びその塩、エデト酸及びその塩、亜硫酸水素ナトリウム、没食子酸プロピル等が挙げられる。
着色剤としては、例えばタール色素、三二酸化鉄、カラメル等が挙げられる。
香料としては、例えばアップルフレーバー等が挙げられる。
矯味剤としては、例えばクエン酸及びその塩、Ｌ−グルタミン酸及びその塩、ｌ−メントール等が挙げられる。
保存剤としては、例えば安息香酸及びその塩、パラベン等が挙げられる。The oral liquid composition of the present invention may further contain other medicinal ingredients, sweeteners, pH adjusters, antioxidants, colorants, fragrances, flavoring agents, preservatives, water and the like. Here, as other medicinal ingredients, aloe, fennel, turmeric, oyak, engosaku, ages, ogi, seisei, onji, guarana, kokushi, jiou, euchu, amarogentin, ougon, autaku, ouren, gajutsu, caskara sagrada, Cuckoo, Cascarilla, Kanocho grass, Calamon, Kyokyo, Kijitsu, Kyonin, Kihada, Kuko, Kukujin, Keigai, Ketsumeishi, Kengoshi, Gentiana, Gennoshouko, Kojijin, Koubushi, Kokuboku, Gouo, Goshitsu, Goshyu, Colombia, Grumpy , Sanshishi, Saffron, Salamander, Sandscon, Giant, Sikon, Jishyu, Shisoshi, Shazen (Psyllium), Jia incense, Shouma, Sehi, Sekishokon, Senega, Senkyu, Senkoutsu, Centaurium grass Assembly, senbo, senso, senna, suzutsu, sakuhakuhi, soyou, daiou, daikon, chimo, chiletta, chimpi, spruce, sushi, tokon, nigaki, peony, peony, belladonnacon, henoposi oil, yakchi, yutan, mugwort , Bitter tincture, hops, homica, bowie, maou, mokutsu, mokko, yokuinin, ryutan, gentian, luzonka, forsythia, rokjou, royal jelly and the like.
Examples of the sweetening agent include sucrose, lactose, fructose, glucose, honey, sorbitol, maltitol, erythritol, xylitol, trehalose, saccharin and its salts, aspartame, acesulfame K, stevia extract and the like.
As a pH adjuster, what can adjust pH to 4-7, especially 5-6 is mentioned.
Examples of the antioxidant include ascorbic acid and its salt, erythorbic acid and its salt, edetic acid and its salt, sodium bisulfite, propyl gallate and the like.
Examples of the colorant include tar pigments, iron sesquioxide, and caramel.
As a fragrance | flavor, an apple flavor etc. are mentioned, for example.
Examples of the corrigent include citric acid and salts thereof, L-glutamic acid and salts thereof, and l-menthol.
Examples of preservatives include benzoic acid and its salts, parabens and the like.

本発明の経口液剤組成物は、前記の原料を混合して水溶液の形態にすることにより製造することができる。本発明により得られる液剤組成物は、配合される生薬等の薬理作用により、例えば滋養強壮用の経口液剤組成物などとして利用できる。   The oral liquid composition of this invention can be manufactured by mixing the said raw material and making it the form of aqueous solution. The liquid composition obtained by the present invention can be used, for example, as an oral liquid composition for nourishing tonics due to the pharmacological action of a crude drug or the like to be blended.

次に参考例、実施例及び比較例を挙げて本発明を詳細に説明するが、本発明はこれらに限定されるものではない。   Next, although a reference example, an Example, and a comparative example are given and this invention is demonstrated in detail, this invention is not limited to these.

参考例１
精製水２０ｍＬに、人参エキス（人参エキス・日本粉末製）４５０ｍｇ（原生薬換算値３０００ｍｇ）、シャクヤクエキス（シャクヤクエキス−Ａ・日本粉末製）１２５ｍｇ（原生薬換算値５００ｍｇ）、トウキエキス（トウキ軟エキス・アルプス薬品製）１５１．５ｍｇ（原生薬換算値５００ｍｇ）、ショウキョウエキス（ショウキョウ流エキス・日本粉末製）０．５ｍＬ（原生薬換算値５００ｍｇ）、タイソウエキス（タイソウ流エキス・日本粉末製）１．０ｍＬ（原生薬換算値１０００ｍｇ）、ケイヒエキス（ケイヒ流エキス・日本粉末製）０．５ｍＬ（原生薬換算値５００ｍｇ）、ショ糖脂肪酸エステル（ＤＫエステルＳＳ・第一工業製）５．０ｍｇ、モノグリセリン脂肪酸エステル（ポエムＭ−１００・理研ビタミン製）５．０ｍｇ、グリチルリチン酸二カリウム（グリチルリチン酸二カリウム・アルプス薬品製）５．０ｍｇ、クエン酸３０ｍｇを加え、攪拌溶解した。これにクエン酸ナトリウムを加えｐＨ５．５に調節し、さらに精製水（常温）適量を加えて全量３０ｍＬ（比重：１．０５）として経口液剤を製造した。Reference example 1
In 20 mL of purified water, 450 mg of ginseng extract (carrot extract, made in Japan powder) (powder equivalent value 3000 mg), peony extract (peony extract-A, made in Japan powder) 125 mg (powder equivalent value 500 mg), toki extract (toki soft) Extract / Alps Yakuhin) 151.5 mg (powder equivalent value 500 mg), Pepper extract (shower flow extract, made in Japan powder) 0.5 mL (powder equivalent value 500 mg), tiso extract (tassault extract / powder) Manufactured) 1.0 mL (powder equivalent value 1000 mg), keihi extract (Keihi style extract, made in Japan powder) 0.5 mL (powder equivalent value 500 mg), sucrose fatty acid ester (DK ester SS, manufactured by Daiichi Kogyo) 5 .0mg, Monoglycerin fatty acid ester (Poem M-100, manufactured by Riken Vitamin) 5.0m , Dipotassium glycyrrhizinate (manufactured dipotassium glycyrrhizinate-Alps Pharmaceutical) 5.0 mg, citric acid 30mg were added and stirred to dissolve. Sodium citrate was added thereto to adjust the pH to 5.5, and an appropriate amount of purified water (room temperature) was further added to prepare an oral solution with a total volume of 30 mL (specific gravity: 1.05).

比較例１
表１の処方に従い、モノグリセリン脂肪酸エステルを加えない他は参考例１と同様に経口液剤を製造した。Comparative Example 1
According to the formulation of Table 1, an oral solution was prepared in the same manner as in Reference Example 1 except that no monoglycerin fatty acid ester was added.

比較例２
表１の処方に従い、ショ糖脂肪酸エステルを加えない他は参考例１と同様に経口液剤を製造した。Comparative Example 2
According to the formulation in Table 1, an oral solution was prepared in the same manner as in Reference Example 1 except that sucrose fatty acid ester was not added.

比較例３
表１の処方に従い、グリチルリチン酸二カリウムを加えない他は参考例１と同様に経口液剤を製造した。Comparative Example 3
According to the formulation in Table 1, an oral solution was prepared in the same manner as in Reference Example 1 except that dipotassium glycyrrhizinate was not added.

比較例４
表１の処方に従い、モノグリセリン脂肪酸エステル及びショ糖脂肪酸エステルに代替し、ポリエチレングリコール脂肪酸エステルを加える他は参考例１と同様に経口液剤を製造した。Comparative Example 4
According to the formulation in Table 1, an oral solution was prepared in the same manner as in Reference Example 1 except that polyethylene glycol fatty acid ester was added instead of monoglycerin fatty acid ester and sucrose fatty acid ester.

試験例１
参考例１及び比較例１〜４で得られた経口液剤を製造直後並びに５℃及び６０℃で１ヶ月間暗所保存した後、各経口液剤の外観安定性を目視にて評価した。外観安定性は、沈殿が生じなかったものを○、沈殿が生じたものを×で示した。結果を表１に示す。Test example 1
After the oral solutions obtained in Reference Example 1 and Comparative Examples 1 to 4 were stored in the dark immediately after production and at 5 ° C. and 60 ° C. for 1 month, the appearance stability of each oral solution was visually evaluated. Appearance stability was indicated by ◯ when no precipitation occurred, and by x when precipitation occurred. The results are shown in Table 1.

Figure 2007135774
Figure 2007135774

ショ糖脂肪酸エステル、モノグリセリン脂肪酸エステル及びグリチルリチン酸二カリウムを配合した人参及びシャクヤク等の生薬含有経口液剤（参考例１）においては、５℃１ヶ月及び６０℃１ヶ月の双方で沈殿を認めず、外観安定性が良好であった。一方、参考例１からモノグリセリン脂肪酸エステル（比較例１）、ショ糖脂肪酸エステル（比較例２）、グリチルリチン酸二カリウム（比較例３）を配合しない経口液剤では、５℃１ヶ月で沈殿を認めた。また、比較例１及び２では、６０℃１ヶ月でも沈殿を認めた。さらに、ショ糖脂肪酸エステル、モノグリセリン脂肪酸エステルのかわりにポリエチレングリコール脂肪酸エステルを配合した経口液剤（比較例４）においては５℃１ヶ月で沈殿を認めた。   In oral liquids containing herbal medicine such as ginseng and peonies blended with sucrose fatty acid ester, monoglycerin fatty acid ester and dipotassium glycyrrhizinate (Reference Example 1), no precipitation was observed both at 5 ° C for 1 month and at 60 ° C for 1 month. The appearance stability was good. On the other hand, in oral liquid preparations containing no monoglycerin fatty acid ester (Comparative Example 1), sucrose fatty acid ester (Comparative Example 2), or dipotassium glycyrrhizinate (Comparative Example 3) from Reference Example 1, precipitation was observed at 5 ° C. for 1 month. It was. In Comparative Examples 1 and 2, precipitation was observed even at 60 ° C. for 1 month. Further, in the oral liquid preparation (Comparative Example 4) containing polyethylene glycol fatty acid ester instead of sucrose fatty acid ester and monoglycerin fatty acid ester, precipitation was observed at 5 ° C. for one month.

実施例１
精製水２０ｍＬに、人参エキス（人参エキス・日本粉末製）４５０ｍｇ（原生薬換算値３０００ｍｇ）、シャクヤクエキス（シャクヤクエキス−Ａ・日本粉末製）１２５ｍｇ（原生薬換算値５００ｍｇ）、トウキエキス（トウキ軟エキス・アルプス薬品製）１５１．５ｍｇ（原生薬換算値５００ｍｇ）、ショウキョウエキス（ショウキョウ流エキス・日本粉末製）０．５ｍＬ（原生薬換算値５００ｍｇ）、タイソウエキス（タイソウ流エキス・日本粉末製）１．０ｍＬ（原生薬換算値１０００ｍｇ）、ケイヒエキス（ケイヒ流エキス・日本粉末製）０．５ｍＬ（原生薬換算値５００ｍｇ）、ショ糖脂肪酸エステル（ＤＫエステルＳＳ・第一工業製）５．０ｍｇ、モノグリセリン脂肪酸エステル（ポエムＭ−１００・理研ビタミン製）５．０ｍｇ、グリチルリチン酸二カリウム（グリチルリチン酸二カリウム・アルプス薬品）５．０ｍｇ、ポリオキシエチレン硬化ヒマシ油（ＨＣＯ−６０・日本サーファクタント）２０．０ｍｇ、ポリビニルピロリドン（コリドン２５・ＢＡＳＦジャパン）１００．０ｍｇ、クエン酸３０ｍｇを加え、攪拌溶解した。これにクエン酸ナトリウムを加えｐＨ５．５に調節し、さらに精製水（常温）適量を加えて全量３０ｍＬ（比重：１．０５）として経口液剤を製造した。Example 1
In 20 mL of purified water, 450 mg of ginseng extract (carrot extract, made in Japan powder) (powder equivalent value 3000 mg), peony extract (peony extract-A, made in Japan powder) 125 mg (powder equivalent value 500 mg), toki extract (toki soft) Extract / Alps Yakuhin) 151.5 mg (powder equivalent value 500 mg), Pepper extract (shower flow extract, made in Japan powder) 0.5 mL (powder equivalent value 500 mg), tiso extract (tassault extract / powder) Manufactured) 1.0 mL (powder equivalent value 1000 mg), keihi extract (Keihi style extract, made in Japan powder) 0.5 mL (powder equivalent value 500 mg), sucrose fatty acid ester (DK ester SS, manufactured by Daiichi Kogyo) 5 .0mg, Monoglycerin fatty acid ester (Poem M-100, manufactured by Riken Vitamin) 5.0m , Dipotassium glycyrrhizinate (dipotassium glycyrrhizinate / Alps Chemicals) 5.0 mg, polyoxyethylene hydrogenated castor oil (HCO-60, Nippon Surfactant) 20.0 mg, polyvinylpyrrolidone (Kollidon 25 / BASF Japan) 100.0 mg, 30 mg of acid was added and dissolved by stirring. Sodium citrate was added thereto to adjust the pH to 5.5, and an appropriate amount of purified water (room temperature) was further added to prepare an oral solution with a total volume of 30 mL (specific gravity: 1.05).

比較例５
表２の処方に従い、ポリビニルピロリドンを加えない他は実施例１と同様に経口液剤を製造した。Comparative Example 5
According to the formulation in Table 2, an oral solution was produced in the same manner as in Example 1 except that polyvinylpyrrolidone was not added.

比較例６
表２の処方に従い、ポリビニルピロリドン及びポリオキシエチレン硬化ヒマシ油を加えない他は実施例１と同様に経口液剤を製造した。Comparative Example 6
According to the formulation in Table 2, an oral solution was prepared in the same manner as in Example 1 except that polyvinylpyrrolidone and polyoxyethylene hydrogenated castor oil were not added.

試験例２
実施例１及び比較例５、６で得られた経口液剤を製造直後、５℃で１ヶ月間及び２ヶ月間暗所保存した後、各経口液剤の沈殿又は白濁についての外観安定性を目視にて評価した。外観安定性は、沈殿に関しては、沈殿が生じなかったものを○、沈殿が生じたものを×で示した。白濁に関しては、澄明なものを○、白濁を生じたものを×で示した。結果を表２に示す。Test example 2
Immediately after the oral solutions obtained in Example 1 and Comparative Examples 5 and 6 were stored in the dark at 5 ° C. for 1 month and 2 months, the appearance stability of each oral solution with respect to precipitation or cloudiness was visually observed. And evaluated. Appearance stability was indicated by ○ for the case where precipitation did not occur and x for the case where precipitation occurred. Concerning white turbidity, a clear one is indicated by ○, and a white turbid one is indicated by ×. The results are shown in Table 2.

Figure 2007135774
Figure 2007135774

ショ糖脂肪酸エステル、モノグリセリン脂肪酸エステル及びグリチルリチン酸二カリウムを配合した人参及びシャクヤク等の生薬配合経口液剤（比較例６）では、５℃１ヶ月では沈殿を認めなかったが、５℃２ヶ月後に沈殿を生じた。そこで、沈殿を抑制するためにポリオキシエチレン硬化ヒマシ油を配合（比較例５）し沈殿を抑制したが、新たに白濁が生じるとの問題が生じた。ショ糖脂肪酸エステル、モノグリセリン脂肪酸エステル、グリチルリチン酸二カリウム及びポリオキシエチレン硬化ヒマシ油を配合した人参及びシャクヤク等の生薬配合経口液剤にポリビニルピロリドンを配合（実施例１）することにより、５℃２ヶ月後に沈殿も白濁も認めず、外観安定性が良好な経口液剤処方を得ることができた。   In an oral solution containing herbal medicines such as ginseng and peonies blended with sucrose fatty acid ester, monoglycerin fatty acid ester and dipotassium glycyrrhizinate (Comparative Example 6), precipitation was not observed at 5 ° C for 1 month, but after 5 ° C for 2 months. Precipitation occurred. Then, in order to suppress precipitation, polyoxyethylene hydrogenated castor oil was mix | blended (comparative example 5), and precipitation was suppressed, but the problem that cloudiness newly arises arose. By blending polyvinylpyrrolidone in a herbal medicine blended oral liquid such as ginseng and peonies blended with sucrose fatty acid ester, monoglycerin fatty acid ester, dipotassium glycyrrhizinate and polyoxyethylene hydrogenated castor oil, 5 ° C. After months, neither precipitation nor cloudiness was observed, and an oral solution formulation with good appearance stability could be obtained.

以上より、人参及びシャクヤク等の生薬を配合した経口液剤にショ糖脂肪酸エステル、モノグリセリン脂肪酸エステル、グリチルリチン酸又はその塩、ポリオキシエチレン硬化ヒマシ油及びポリビニルピロリドンを配合することにより、長期間の低温条件下において外観安定性が良好な生薬配合経口液剤を得ることができた。   As mentioned above, long-term low temperature can be obtained by blending sucrose fatty acid ester, monoglycerin fatty acid ester, glycyrrhizic acid or its salt, polyoxyethylene hydrogenated castor oil and polyvinylpyrrolidone into oral liquids containing herbal medicines such as carrots and peonies. Under such conditions, a crude drug-containing oral solution with good appearance stability could be obtained.

Claims (3)

次の成分（Ａ）〜（Ｆ）：
（Ａ）人参、ショウキョウ、タイソウ、シャクヤク、トウキ、及びケイヒから選ばれる１種又は２種以上の生薬
（Ｂ）ショ糖脂肪酸エステル
（Ｃ）モノグリセリン脂肪酸エステル
（Ｄ）グリチルリチン酸又はその塩
（Ｅ）ポリオキシエチレン硬化ヒマシ油
（Ｆ）ポリビニルピロリドン
を含有することを特徴とする経口液剤組成物。The following components (A) to (F):
(A) One or more herbal medicines selected from ginseng, ginger, peony, peony, toki, and keihi (B) sucrose fatty acid ester (C) monoglycerin fatty acid ester (D) glycyrrhizic acid or a salt thereof ( E) An oral liquid composition comprising polyoxyethylene hydrogenated castor oil (F) polyvinylpyrrolidone. 各成分の含有量の相対質量比率が、成分（Ａ）の原生薬換算値としての含有量を１とした場合、成分（Ｂ）、成分（Ｃ）、及び成分（Ｄ）の含有量がそれぞれ０．００００４〜０．０２の範囲内であり、成分（Ｅ）の含有量が０．００００４〜０．２の範囲内であり、成分（Ｆ）の含有量が０．０００４〜０．４の範囲内である請求項１記載の経口液剤組成物。   When the relative mass ratio of the content of each component is 1, the content of the component (A) as an active ingredient conversion value is 1, the content of the component (B), the component (C), and the component (D) is respectively It is in the range of 0.00004 to 0.02, the content of component (E) is in the range of 0.00004 to 0.2, and the content of component (F) is 0.0004 to 0.4. The oral liquid composition according to claim 1, which is within the range. 成分（Ａ）の原生薬換算値としての含有量が５〜２５質量％であり、成分（Ｂ）、成分（Ｃ）、及び成分（Ｄ）の含有量がそれぞれ０．００１〜０．１質量％であり、成分（Ｅ）の含有量が０．００１〜１質量％であり、成分（Ｆ）の含有量が０．０１〜２質量％である請求項１又は２記載の経口液剤組成物。   The content of the component (A) as a raw drug equivalent is 5 to 25% by mass, and the content of the component (B), the component (C), and the component (D) is 0.001 to 0.1 mass, respectively. The oral liquid composition according to claim 1 or 2, wherein the content of the component (E) is 0.001 to 1% by mass and the content of the component (F) is 0.01 to 2% by mass. .
JP2008516559A 2006-05-23 2007-05-21 Herbal medicine-containing oral solution composition Pending JPWO2007135774A1 (en)

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