WO2015125757A1 - Internal liquid agent - Google Patents
Internal liquid agent Download PDFInfo
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- WO2015125757A1 WO2015125757A1 PCT/JP2015/054207 JP2015054207W WO2015125757A1 WO 2015125757 A1 WO2015125757 A1 WO 2015125757A1 JP 2015054207 W JP2015054207 W JP 2015054207W WO 2015125757 A1 WO2015125757 A1 WO 2015125757A1
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- ambroxol hydrochloride
- polyethylene glycol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/10—Expectorants
Definitions
- the present invention relates to an internal solution containing ambroxol hydrochloride.
- Ambroxol hydrochloride is an airway lubrication expectorant that lubricates the airway wall and facilitates discharge of sputum and pus by promoting airway fluid secretion promoting action, lung surfactant secretion promoting action and ciliary movement, in addition to tablets, It is used in various dosage forms such as fine granules, liquids, syrups, and sustained sustained release capsules.
- Ambroxol hydrochloride is widely accepted in Japan and other Southeast Asian countries as an internal solution and pediatric syrup from the viewpoint of ease of administration.
- an aqueous liquid preparation containing ambroxol hydrochloride has a problem that the appearance is changed because coloring is observed by light irradiation.
- a method of suppressing coloring by suppressing light irradiation and a method of decreasing the color change rate by coloring a solution before reaction by light irradiation.
- a method using a light-shielding container such as a brown glass bottle as a method for suppressing light irradiation, but it is difficult to observe the state of the chemical solution.
- the glass bottle is inconvenient in terms of weight, but there is no other solution, and a method using a light-shielding container is widely used as a means for suppressing light irradiation with respect to an aqueous liquid agent containing ambroxol hydrochloride as an active ingredient. Is selected.
- Non-patent Document 1 a pigment used for coloring a preparation generates a precipitate when ambroxol hydrochloride and yellow No. 5 are blended simultaneously.
- An object of the present invention is to provide a stable oral solution that suppresses color change due to light irradiation of ambroxol hydrochloride and does not generate a precipitate.
- a liquid agent containing ambroxol hydrochloride, a dye and polyethylene glycol has a problem that the dye fades when heated.
- the present inventors have found that by adding gallic acid or a derivative thereof, discoloration of the dye due to heat in a liquid preparation containing ambroxol hydrochloride, the dye and polyethylene glycol can be suppressed.
- the present invention has been completed.
- the present invention includes the following.
- An oral solution characterized by containing ambroxol hydrochloride, a pigment, and polyethylene glycol.
- One or two pigments selected from amaranth, erythrosine, allura red AC, new coccin, phloxine, rose bengal, acid red, tartrazine, sunset yellow FCF, first green FCF, brilliant blue FCF, indigo carmine
- the internal liquid preparation described in (1) above.
- an internal liquid preparation in which color change of ambroxol hydrochloride due to light irradiation is suppressed, precipitation is not generated, discoloration of a pigment due to heat is suppressed, and bitterness of ambroxol hydrochloride is suppressed. Became possible.
- the content of ambroxol hydrochloride used in the present invention is preferably 0.1 to 5% by mass relative to the total amount of the liquid, and is 0.2 to 1% by mass from the viewpoint of the dosage of ambroxol hydrochloride and the flavor of the preparation. Is more preferable.
- the polyethylene glycol used in the present invention preferably has an average molecular weight of 200 to 20000, more preferably 1000 to 6000 from the viewpoint of the precipitation suppressing effect. Among these, the range of 1000 to 1600 is particularly preferable from the viewpoint of ingestion.
- the blending amount of polyethylene glycol is preferably 5 to 90 parts by mass, more preferably 10 to 60 parts by mass with respect to 1 part by mass of ambroxol hydrochloride. If the amount is less than 5 parts by mass, the bitterness-inhibiting effect may be weak.
- the colorant used in the present invention is not particularly limited, and examples thereof include amaranth, erythrosin, allura red AC, new coxin, phloxine, rose bengal, acid red, tartrazine, sunset yellow FCF, first green FCF, brilliant blue FCF, indigo carmine and the like. These can be used alone or in combination of two or more.
- the content of the dye used in the present invention is preferably 0.0001 to 0.1 parts by mass, more preferably 0.0005 to 0.005 parts by mass with respect to 1 part by mass of ambroxol hydrochloride. If the amount is less than 0.0001 part by mass, a sufficient coloring suppression effect may not be obtained, and if the amount is more than 0.1 part by mass, it may not be preferable from the viewpoint of safety.
- the gallic acid or derivative thereof used in the present invention is not particularly limited, and examples thereof include ethyl gallate, propyl gallate, isoamyl gallate, and epigallocatechin gallate.
- the blending amount of gallic acid and its derivative is preferably 0.001 to 0.3 parts by mass, more preferably 0.003 to 0.15 parts by mass with respect to 1 part by mass of ambroxol hydrochloride. When the amount is less than 0.001 part by mass, the effect of suppressing the fading of the dye may be weak. When the amount is more than 0.3 part by mass, the deterioration of properties may occur after heat transformation.
- the pH of the internal solution of the present invention is preferably 2.0 to 7.0, more preferably 3.0 to 5.0.
- a pH adjuster can also be mix
- the pH adjuster include organic acids such as citric acid, malic acid, fumaric acid, tartaric acid, lactic acid and succinic acid and salts thereof, inorganic acids such as phosphoric acid and hydrochloric acid, inorganic bases such as sodium hydroxide, and the like.
- ingredients for the internal use liquid preparation of the present invention include sweeteners, acidulants, thickening stabilizers, antioxidants, coloring agents, flavorings, flavoring agents, preservatives, seasonings, bitterings, fortifiers, solubilizers.
- Additives such as emulsifiers can be appropriately blended within a range not impairing the effects of the present invention.
- the oral solution of the present invention can be prepared by a conventional method, and the method is not particularly limited. Usually, after dissolving polyethylene glycol in a liquid agent, a pigment
- the internal liquid of the present invention suppresses color change due to light irradiation, it is filled in transparent glass bottles and non-light-shielding containers made of plastic such as polyethylene terephthalate, polyacrylate, polyethylene naphthalate, polycarbonate, polyethylene, polypropylene, polyimide, etc. Can be saved.
- plastic such as polyethylene terephthalate, polyacrylate, polyethylene naphthalate, polycarbonate, polyethylene, polypropylene, polyimide, etc.
- the oral solution of the present invention can be applied to various pharmaceutical preparations.
- Example 1 Ambroxol hydrochloride 60 mg, polyethylene glycol 1450 1500 mg, Sunset Yellow FCF 0.083 mg, sorbitol 70% solution 4500 mg, citric acid hydrate 24 mg, sodium benzoate 20 mg are dissolved in purified water, and purified water is added to make a total volume of 10 mL. Then, it was filled into a transparent glass bottle and capped to obtain a clear liquid for internal use.
- Examples 2 to 10 and Comparative Examples 1 to 3 shown in Tables 1-1 to 1-3 were also prepared in the same manner as Example 1.
- Test example 1 (visual observation) Test solutions of Examples 1 to 10 and Comparative Examples 1 to 3 were prepared and visually observed. Tables 2-1 to 2-3 show the state of precipitation for each hour after preparation.
- Example 11 Ambroxol hydrochloride 60 mg, polyethylene glycol 1450 1500 mg, tartrazine 0.083 mg, sorbitol 70% solution 4500 mg, citric acid hydrate 24 mg, sodium benzoate 20 mg were dissolved in purified water, and purified water was added to make a total volume of 10 mL. A transparent glass bottle was filled and capped to obtain a clear oral solution.
- Examples 12 to 18 shown in Tables 3-1 and 3-2 below were also prepared in the same manner as Example 11.
- Test example 2 thermo stability test
- Test solutions of Examples 1, 2 and 11 to 18 were prepared and visually observed. Furthermore, it was stored for 1 week or 4 days at 80 ° C. (relative humidity), and the color change was visually confirmed. The results are shown in Tables 4-1 and 4-2.
- an internal liquid preparation in which the color change of ambroxol hydrochloride due to light irradiation is suppressed, the fading of the pigment due to heat is suppressed, no precipitate is formed, and the bitter taste of ambroxol hydrochloride is suppressed. Became possible.
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Abstract
Description
本発明は、塩酸アンブロキソールを含有する内服液剤に関する。 The present invention relates to an internal solution containing ambroxol hydrochloride.
塩酸アンブロキソールは気道液分泌促進作用、肺サーファクタント分泌促進作用及び線毛運動の活発化により、気道壁を潤滑にして痰や膿を排出しやすくする気道潤滑去痰剤であり、錠剤のほか、細粒や液剤、シロップ剤、持続性のある徐放カプセルなど様々な剤型で用いられている。 Ambroxol hydrochloride is an airway lubrication expectorant that lubricates the airway wall and facilitates discharge of sputum and pus by promoting airway fluid secretion promoting action, lung surfactant secretion promoting action and ciliary movement, in addition to tablets, It is used in various dosage forms such as fine granules, liquids, syrups, and sustained sustained release capsules.
塩酸アンブロキソールは日本をはじめとした東南アジアにおいて、服用しやすさの観点から内服液剤や小児用シロップ剤として広く受け入れられている。 Ambroxol hydrochloride is widely accepted in Japan and other Southeast Asian countries as an internal solution and pediatric syrup from the viewpoint of ease of administration.
しかしながら、塩酸アンブロキソールを含有する水性液剤は、光照射により着色が認められるため、外観が変化してしまうという問題がある。外観の変化を抑制するためには、光照射を抑制することで着色を抑える方法や、光照射による反応前の溶液を着色することで色の変化率を小さくする方法が考えられる。 However, an aqueous liquid preparation containing ambroxol hydrochloride has a problem that the appearance is changed because coloring is observed by light irradiation. In order to suppress the change in appearance, there are a method of suppressing coloring by suppressing light irradiation, and a method of decreasing the color change rate by coloring a solution before reaction by light irradiation.
光照射を抑制する方法としては褐色ガラス瓶等の遮光容器を用いる方法があるが、薬液の状態を観察するのは困難である。また、ガラス瓶は重量の面から持ち運びの点で不便であるが、その他の解決方法はなく、塩酸アンブロキソールを有効成分とする水性液剤に対する光照射を抑制する手段としては遮光容器による方法が広く選択されている。 There is a method using a light-shielding container such as a brown glass bottle as a method for suppressing light irradiation, but it is difficult to observe the state of the chemical solution. In addition, the glass bottle is inconvenient in terms of weight, but there is no other solution, and a method using a light-shielding container is widely used as a means for suppressing light irradiation with respect to an aqueous liquid agent containing ambroxol hydrochloride as an active ingredient. Is selected.
また、製剤を着色するのに使用する色素については、塩酸アンブロキソールと黄色５号を同時に配合した場合に、沈殿を生成することが知られている（非特許文献１）。 In addition, it is known that a pigment used for coloring a preparation generates a precipitate when ambroxol hydrochloride and yellow No. 5 are blended simultaneously (Non-patent Document 1).
本発明は、塩酸アンブロキソールの光照射による色変化を抑制し、且つ沈殿を生成することなく安定な内服液剤を提供することを課題とする。 An object of the present invention is to provide a stable oral solution that suppresses color change due to light irradiation of ambroxol hydrochloride and does not generate a precipitate.
本発明者らは、上記課題を解決すべく鋭意検討した結果、ポリエチレングリコールを配合することにより、塩酸アンブロキソールと色素が沈殿を生成せずに安定的に液剤に配合できることを発見した。さらに、ポリエチレングリコールを配合することにより塩酸アンブロキソールの苦味が抑制できることを発見した。 As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that by blending polyethylene glycol, ambroxol hydrochloride and a pigment can be stably blended in a liquid without forming a precipitate. Furthermore, it discovered that the bitterness of ambroxol hydrochloride could be suppressed by mix | blending polyethyleneglycol.
しかしながら、塩酸アンブロキソール、色素及びポリエチレングリコールを含有する液剤は、熱をかけた場合に色素が退色するという問題がある。これに対し本発明者らは鋭意検討した結果、没食子酸又はその誘導体を配合することで、塩酸アンブロキソール、色素及びポリエチレングリコールを含有する液剤における、熱による色素の退色を抑制できることを発見し、本発明を完成するに至った。 However, a liquid agent containing ambroxol hydrochloride, a dye and polyethylene glycol has a problem that the dye fades when heated. On the other hand, as a result of intensive studies, the present inventors have found that by adding gallic acid or a derivative thereof, discoloration of the dye due to heat in a liquid preparation containing ambroxol hydrochloride, the dye and polyethylene glycol can be suppressed. The present invention has been completed.
即ち本発明には下記が含まれる。
（１）塩酸アンブロキソール、色素、及びポリエチレングリコールを含有することを特徴とする内服液剤。
（２）色素が、アマランス、エリスロシン、アルラレッドＡＣ、ニューコクシン、フロキシン、ローズベンガル、アシッドレッド、タートラジン、サンセットイエローＦＣＦ、ファーストグリーンＦＣＦ、ブリリアントブルーＦＣＦ、インジゴカーミンから選ばれる１種又は２種以上である（１）に記載の内服液剤。
（３）ポリエチレングリコールの平均分子量が２００～２００００である（１）又は（２）に記載の内服液剤。
（４）塩酸アンブロキソールの含有量が液剤全量に対して０．１～５質量％である（１）～（３）のいずれか１項に記載の内服液剤。
（５）色素の含有量が塩酸アンブロキソール１質量部に対して０．０００１～０．１質量部である（１）～（４）のいずれか１項に記載の内服液剤。
（６）ポリエチレングリコールの含有量が塩酸アンブロキソール１質量部に対して５～９０質量部である（１）～（５）のいずれか１項に記載の内服液剤。
（７）さらに、没食子酸又はその誘導体を含有することを特徴とする（１）～（６）のいずれか１項に記載の内服液剤。
（８）没食子酸又はその誘導体の含有量が塩酸アンブロキソール１質量部に対して０．００１～０．３質量部であることを特徴とする（７）に記載の内服液剤。
That is, the present invention includes the following.
(1) An oral solution characterized by containing ambroxol hydrochloride, a pigment, and polyethylene glycol.
(2) One or two pigments selected from amaranth, erythrosine, allura red AC, new coccin, phloxine, rose bengal, acid red, tartrazine, sunset yellow FCF, first green FCF, brilliant blue FCF, indigo carmine The internal liquid preparation described in (1) above.
(3) The internal liquid preparation according to (1) or (2), wherein the polyethylene glycol has an average molecular weight of 200 to 20000.
(4) The internal liquid preparation according to any one of (1) to (3), wherein the content of ambroxol hydrochloride is 0.1 to 5% by mass relative to the total amount of the liquid preparation.
(5) The internal liquid preparation according to any one of (1) to (4), wherein the pigment content is 0.0001 to 0.1 parts by mass with respect to 1 part by mass of ambroxol hydrochloride.
(6) The internal liquid preparation according to any one of (1) to (5), wherein the content of polyethylene glycol is 5 to 90 parts by mass with respect to 1 part by mass of ambroxol hydrochloride.
(7) The oral solution according to any one of (1) to (6), further comprising gallic acid or a derivative thereof.
(8) The internal liquid preparation according to (7), wherein the content of gallic acid or a derivative thereof is 0.001 to 0.3 parts by mass with respect to 1 part by mass of ambroxol hydrochloride.
本発明により、光照射による塩酸アンブロキソールの色変化が抑制され、沈殿の生成がなく、熱による色素の退色が抑制され、且つ塩酸アンブロキソールの苦味が抑制された内服液剤を提供することが可能になった。 According to the present invention, there is provided an internal liquid preparation in which color change of ambroxol hydrochloride due to light irradiation is suppressed, precipitation is not generated, discoloration of a pigment due to heat is suppressed, and bitterness of ambroxol hydrochloride is suppressed. Became possible.
本発明に用いる塩酸アンブロキソールの含有量は液剤全量に対して好ましくは０．１～５質量％であり、塩酸アンブロキソールの投与量と製剤の風味の点から０．２～１質量％がさらに好ましい。 The content of ambroxol hydrochloride used in the present invention is preferably 0.1 to 5% by mass relative to the total amount of the liquid, and is 0.2 to 1% by mass from the viewpoint of the dosage of ambroxol hydrochloride and the flavor of the preparation. Is more preferable.
本発明に用いるポリエチレングリコールは、沈殿抑制効果の点から平均分子量が２００～２００００であることが好ましく、１０００～６０００であることがより好ましい。この中でも１０００～１６００であることが服用性の面から特に好ましい。ポリエチレングリコールの配合量は、塩酸アンブロキソール１質量部に対して好ましくは５～９０質量部であり、より好ましくは１０～６０質量部である。５質量部より少ないと苦味抑制効果が弱いことがあり、９０質量部より多いと高分子様の不快味が強くなることがあるので好ましくない。 The polyethylene glycol used in the present invention preferably has an average molecular weight of 200 to 20000, more preferably 1000 to 6000 from the viewpoint of the precipitation suppressing effect. Among these, the range of 1000 to 1600 is particularly preferable from the viewpoint of ingestion. The blending amount of polyethylene glycol is preferably 5 to 90 parts by mass, more preferably 10 to 60 parts by mass with respect to 1 part by mass of ambroxol hydrochloride. If the amount is less than 5 parts by mass, the bitterness-inhibiting effect may be weak.
本発明に用いる色素は特に限定されないが、アマランス、エリスロシン、アルラレッドＡＣ、ニューコクシン、フロキシン、ローズベンガル、アシッドレッド、タートラジン、サンセットイエローＦＣＦ、ファーストグリーンＦＣＦ、ブリリアントブルーＦＣＦ、インジゴカーミン等が挙げられ、これらは単独で又は２種以上使用できる。本発明に用いる色素の含有量は、塩酸アンブロキソールの１質量部に対して好ましくは０．０００１～０．１質量部であり、さらに好ましくは０．０００５～０．００５質量部である。０．０００１質量部より少ないと十分な着色抑制効果が得られないことがあり、０．１質量部より多いと安全性等の点から好ましくないこともあり得る。 The colorant used in the present invention is not particularly limited, and examples thereof include amaranth, erythrosin, allura red AC, new coxin, phloxine, rose bengal, acid red, tartrazine, sunset yellow FCF, first green FCF, brilliant blue FCF, indigo carmine and the like. These can be used alone or in combination of two or more. The content of the dye used in the present invention is preferably 0.0001 to 0.1 parts by mass, more preferably 0.0005 to 0.005 parts by mass with respect to 1 part by mass of ambroxol hydrochloride. If the amount is less than 0.0001 part by mass, a sufficient coloring suppression effect may not be obtained, and if the amount is more than 0.1 part by mass, it may not be preferable from the viewpoint of safety.
本発明に用いる没食子酸又はその誘導体は特に限定されないが、例えば没食子酸エチル、没食子酸プロピル、没食子酸イソアミル、没食子酸エピガロカテキンが挙げられる。没食子酸及びその誘導体の配合量は、塩酸アンブロキソールの１質量部に対して好ましくは０．００１～０．３質量部であり、さらに好ましくは０．００３～０．１５質量部である。０．００１質量部より少ないと色素の退色抑制効果が弱いことがあり、０．３質量部より多いと熱経変後に性状の悪化が懸念されることがある。 The gallic acid or derivative thereof used in the present invention is not particularly limited, and examples thereof include ethyl gallate, propyl gallate, isoamyl gallate, and epigallocatechin gallate. The blending amount of gallic acid and its derivative is preferably 0.001 to 0.3 parts by mass, more preferably 0.003 to 0.15 parts by mass with respect to 1 part by mass of ambroxol hydrochloride. When the amount is less than 0.001 part by mass, the effect of suppressing the fading of the dye may be weak. When the amount is more than 0.3 part by mass, the deterioration of properties may occur after heat transformation.
本発明の内服液剤のｐＨは、好ましくは２．０～７．０であり、より好ましくは３．０～５．０である。なお、本発明の液剤のｐＨを上記範囲に保つために、必要に応じてｐＨ調整剤が配合することもできる。ｐＨ調整剤としては、クエン酸、リンゴ酸、フマル酸、酒石酸、乳酸、コハク酸などの有機酸及びそれらの塩類、リン酸、塩酸などの無機酸、水酸化ナトリウムなどの無機塩基などが挙げられる。 The pH of the internal solution of the present invention is preferably 2.0 to 7.0, more preferably 3.0 to 5.0. In addition, in order to keep pH of the liquid agent of this invention in the said range, a pH adjuster can also be mix | blended as needed. Examples of the pH adjuster include organic acids such as citric acid, malic acid, fumaric acid, tartaric acid, lactic acid and succinic acid and salts thereof, inorganic acids such as phosphoric acid and hydrochloric acid, inorganic bases such as sodium hydroxide, and the like. .
本発明の内服液剤にはその他の成分として、甘味料、酸味料、増粘安定剤、酸化防止剤、着色剤、香料、矯味剤、保存料、調味料、苦味料、強化剤、可溶化剤、乳化剤などの添加物を本発明の効果を損なわない範囲で適宜に配合することができる。 Other ingredients for the internal use liquid preparation of the present invention include sweeteners, acidulants, thickening stabilizers, antioxidants, coloring agents, flavorings, flavoring agents, preservatives, seasonings, bitterings, fortifiers, solubilizers. Additives such as emulsifiers can be appropriately blended within a range not impairing the effects of the present invention.
本発明の内服液剤は、常法により調製することができ、その方法は特に限定されるものではない。通常、液剤中にポリエチレングリコールを溶解させた後に色素及び各成分を加え、ｐＨを調整し、残りの精製水を加えて容量調整し、必要に応じてろ過処理することにより得られる。 The oral solution of the present invention can be prepared by a conventional method, and the method is not particularly limited. Usually, after dissolving polyethylene glycol in a liquid agent, a pigment | dye and each component are added, pH is adjusted, the remaining purified water is added, volume is adjusted, and it obtains by filtering as needed.
本発明の内服液剤は光照射による色変化が抑制されるため、透明のガラス瓶や、ポリエチレンテレフタレート、ポリアクリレート、ポリエチレンナフタレート、ポリカーボネート、ポリエチレン、ポリプロピレン、ポリイミド等のプラスチック製の非遮光容器等に充填、保存することができる。 Since the internal liquid of the present invention suppresses color change due to light irradiation, it is filled in transparent glass bottles and non-light-shielding containers made of plastic such as polyethylene terephthalate, polyacrylate, polyethylene naphthalate, polycarbonate, polyethylene, polypropylene, polyimide, etc. Can be saved.
本発明の内服液剤は、医薬品の各種製剤に適用することができる。 The oral solution of the present invention can be applied to various pharmaceutical preparations.
以下に実施例、比較例及び試験例を挙げ、本発明をさらに詳しく説明する。 Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples and Test Examples.
実施例１
塩酸アンブロキソール６０ｍｇ、ポリエチレングリコール１４５０ １５００ｍｇ、サンセットイエローＦＣＦ０．０８３ｍｇ、ソルビトール７０％溶液４５００ｍｇ、クエン酸水和物２４ｍｇ、安息香酸ナトリウム２０ｍｇを精製水に溶解し、精製水を加えて全量を１０ｍＬとし、透明のガラス瓶に充填しキャップをし、澄明な内服液剤を得た。
Example 1
Ambroxol hydrochloride 60 mg, polyethylene glycol 1450 1500 mg, Sunset Yellow FCF 0.083 mg, sorbitol 70% solution 4500 mg, citric acid hydrate 24 mg, sodium benzoate 20 mg are dissolved in purified water, and purified water is added to make a total volume of 10 mL. Then, it was filled into a transparent glass bottle and capped to obtain a clear liquid for internal use.
以下表１－１～１－３に示す実施例２～１０、比較例１～３も実施例１と同様に調製した。 Hereinafter, Examples 2 to 10 and Comparative Examples 1 to 3 shown in Tables 1-1 to 1-3 were also prepared in the same manner as Example 1.
試験例１（目視観察）
実施例１～１０、比較例１～３の試験液を調製し、目視による観察を行った。調製後の時間ごとの沈殿析出の様子を表２－１～２－３に示す。
Test example 1 (visual observation)
Test solutions of Examples 1 to 10 and Comparative Examples 1 to 3 were prepared and visually observed. Tables 2-1 to 2-3 show the state of precipitation for each hour after preparation.
表２－１～２－３から明らかなように、実施例１～１０は、比較例１～３と比較して沈殿の析出は見られず、性状安定性が良好であった。この結果からポリエチレングリコール１４５０を一定量以上配合することで、塩酸アンブロキソール含有液剤にサンセットイエローＦＣＦもしくはアルラレッドＡＣを沈殿の析出を起こすことなく配合することが可能であることが明らかとなった。 As is clear from Tables 2-1 to 2-3, in Examples 1 to 10, precipitation was not observed as compared with Comparative Examples 1 to 3, and the property stability was good. From this result, it became clear that by adding a certain amount or more of polyethylene glycol 1450, it was possible to add Sunset Yellow FCF or Alla Red AC to an ambroxol hydrochloride-containing liquid agent without causing precipitation. .
実施例１１
塩酸アンブロキソール６０ｍｇ、ポリエチレングリコール１４５０ １５００ｍｇ、タートラジン０．０８３ｍｇ、ソルビトール７０％溶液４５００ｍｇ、クエン酸水和物２４ｍｇ、安息香酸ナトリウム２０ｍｇを精製水に溶解し、精製水を加えて全量を１０ｍＬとし、透明のガラス瓶に充填しキャップをし、澄明な内服液剤を得た。
Example 11
Ambroxol hydrochloride 60 mg, polyethylene glycol 1450 1500 mg, tartrazine 0.083 mg, sorbitol 70% solution 4500 mg, citric acid hydrate 24 mg, sodium benzoate 20 mg were dissolved in purified water, and purified water was added to make a total volume of 10 mL. A transparent glass bottle was filled and capped to obtain a clear oral solution.
以下表３－１及び３－２に示す実施例１２～１８も実施例１１と同様に調製した。 Examples 12 to 18 shown in Tables 3-1 and 3-2 below were also prepared in the same manner as Example 11.
試験例２（熱安定性試験）
実施例１、２及び１１～１８の試験液を調製し、目視による観察を行った。さらに８０℃（相対湿度成り行き）で１週間もしくは４日保管し、色の変化を目視で確認した。結果を表４－１及び４－２に示す。
Test example 2 (thermal stability test)
Test solutions of Examples 1, 2 and 11 to 18 were prepared and visually observed. Furthermore, it was stored for 1 week or 4 days at 80 ° C. (relative humidity), and the color change was visually confirmed. The results are shown in Tables 4-1 and 4-2.
表５の結果からも明らかなように、実施例１、２及び１１～１８は、色素添加時の沈殿析出は見られず、性状安定性が良好であった。さらに一定量以上没食子酸プロピルを配合した実施例１２～１６は、色素の退色を起こさないことが分かった。この結果から、塩酸アンブロキソール、ポリエチレングリコール及び色素を含有する液剤における色素の退色は、没食子酸プロピルを配合することにより抑制できることが明らかとなった。 As is apparent from the results in Table 5, Examples 1, 2 and 11 to 18 did not show precipitation upon addition of the dye, and had good property stability. Furthermore, it was found that Examples 12 to 16 in which a certain amount or more of propyl gallate was blended did not cause color fading. From this result, it became clear that the fading of the pigment | dye in the liquid agent containing an ambroxol hydrochloride, polyethyleneglycol, and a pigment | dye can be suppressed by mix | blending propyl gallate.
本発明により、光照射による塩酸アンブロキソールの色変化が抑制され、熱による色素の退色が抑制され、沈殿が生成せず、且つ塩酸アンブロキソールの苦味が抑制された内服液剤を提供することが可能になった。 According to the present invention, there is provided an internal liquid preparation in which the color change of ambroxol hydrochloride due to light irradiation is suppressed, the fading of the pigment due to heat is suppressed, no precipitate is formed, and the bitter taste of ambroxol hydrochloride is suppressed. Became possible.
Claims (8)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2016504098A JP6372559B2 (en) | 2014-02-18 | 2015-02-17 | Oral solution |
| PH12016501529A PH12016501529B1 (en) | 2014-02-18 | 2016-08-03 | Internal liquid agent |
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| JP2014-028361 | 2014-02-18 | ||
| JP2014028361 | 2014-02-18 |
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| JP (1) | JP6372559B2 (en) |
| PH (1) | PH12016501529B1 (en) |
| WO (1) | WO2015125757A1 (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08337522A (en) * | 1995-06-13 | 1996-12-24 | Ota Seiyaku Kk | Aqueous liquid preparation of ambroxole hydrochloride |
| JP2000007561A (en) * | 1998-06-18 | 2000-01-11 | Nissho Corp | Ambroxol hydrochloride aqueous solution preparation |
| US20050075403A1 (en) * | 2003-10-02 | 2005-04-07 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Ambroxol for the treatment of inflammation in the pharynx |
| EP1543826A1 (en) * | 2003-12-16 | 2005-06-22 | Advance Holdings Limited | Concentrated aqueous solution of ambroxol |
| JP2007536296A (en) * | 2004-05-03 | 2007-12-13 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Topical preparation containing ambroxol |
-
2015
- 2015-02-17 JP JP2016504098A patent/JP6372559B2/en active Active
- 2015-02-17 WO PCT/JP2015/054207 patent/WO2015125757A1/en not_active Ceased
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2016
- 2016-08-03 PH PH12016501529A patent/PH12016501529B1/en unknown
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08337522A (en) * | 1995-06-13 | 1996-12-24 | Ota Seiyaku Kk | Aqueous liquid preparation of ambroxole hydrochloride |
| JP2000007561A (en) * | 1998-06-18 | 2000-01-11 | Nissho Corp | Ambroxol hydrochloride aqueous solution preparation |
| US20050075403A1 (en) * | 2003-10-02 | 2005-04-07 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Ambroxol for the treatment of inflammation in the pharynx |
| EP1543826A1 (en) * | 2003-12-16 | 2005-06-22 | Advance Holdings Limited | Concentrated aqueous solution of ambroxol |
| JP2007536296A (en) * | 2004-05-03 | 2007-12-13 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Topical preparation containing ambroxol |
Non-Patent Citations (1)
| Title |
|---|
| IYAKUHIN INTERVIEW FORM ALIMEZINE SYRUP 0.05%, September 2012 (2012-09-01), pages 4 - 10 * |
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| PH12016501529A1 (en) | 2017-02-06 |
| JP6372559B2 (en) | 2018-08-15 |
| PH12016501529B1 (en) | 2017-02-06 |
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