WO2015125754A1 - Internal liquid agent - Google Patents
Internal liquid agent Download PDFInfo
- Publication number
- WO2015125754A1 WO2015125754A1 PCT/JP2015/054203 JP2015054203W WO2015125754A1 WO 2015125754 A1 WO2015125754 A1 WO 2015125754A1 JP 2015054203 W JP2015054203 W JP 2015054203W WO 2015125754 A1 WO2015125754 A1 WO 2015125754A1
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- WO
- WIPO (PCT)
- Prior art keywords
- ambroxol hydrochloride
- tartrazine
- mass
- liquid agent
- present
- Prior art date
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- 239000007788 liquid Substances 0.000 title claims abstract description 22
- QNVKOSLOVOTXKF-UHFFFAOYSA-N 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexan-1-ol;hydron;chloride Chemical compound Cl.NC1=C(Br)C=C(Br)C=C1CNC1CCC(O)CC1 QNVKOSLOVOTXKF-UHFFFAOYSA-N 0.000 claims abstract description 23
- 229960000985 ambroxol hydrochloride Drugs 0.000 claims abstract description 23
- 235000012756 tartrazine Nutrition 0.000 claims abstract description 13
- 239000004149 tartrazine Substances 0.000 claims abstract description 13
- UJMBCXLDXJUMFB-GLCFPVLVSA-K tartrazine Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1\N=N\C1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-GLCFPVLVSA-K 0.000 claims abstract description 13
- 229960000943 tartrazine Drugs 0.000 claims abstract description 12
- 238000002360 preparation method Methods 0.000 claims description 13
- 229940100688 oral solution Drugs 0.000 claims description 4
- 238000004040 coloring Methods 0.000 abstract description 6
- 239000003795 chemical substances by application Substances 0.000 abstract description 5
- 239000002244 precipitate Substances 0.000 abstract description 4
- 239000000243 solution Substances 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- -1 sodium hydroxide Chemical compound 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 239000000049 pigment Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- OIQPTROHQCGFEF-QIKYXUGXSA-L Sunset Yellow FCF Chemical compound [Na+].[Na+].OC1=CC=C2C=C(S([O-])(=O)=O)C=CC2=C1\N=N\C1=CC=C(S([O-])(=O)=O)C=C1 OIQPTROHQCGFEF-QIKYXUGXSA-L 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 239000003172 expectorant agent Substances 0.000 description 2
- 230000003419 expectorant effect Effects 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 235000012751 sunset yellow FCF Nutrition 0.000 description 2
- 239000004173 sunset yellow FCF Substances 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000004642 Polyimide Substances 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 208000032400 Retinal pigmentation Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000001886 ciliary effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 239000003580 lung surfactant Substances 0.000 description 1
- 229940066294 lung surfactant Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920003207 poly(ethylene-2,6-naphthalate) Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000011112 polyethylene naphthalate Substances 0.000 description 1
- 229920000139 polyethylene terephthalate Polymers 0.000 description 1
- 239000005020 polyethylene terephthalate Substances 0.000 description 1
- 229920001721 polyimide Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Classifications
-
- 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
-
- 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
-
- 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
- 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
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- 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
-
- 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.
- An expectorant containing ambroxol hydrochloride is widely accepted as a liquid for internal use and a syrup for children from the viewpoint of ease of taking.
- 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.
- 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.
- tartrazine which is a specific pigment, suppresses color change due to light irradiation of ambroxol hydrochloride, and can be stably used as a liquid without forming a precipitate. It discovered that it could mix
- the present invention includes the following.
- An internal liquid preparation containing ambroxol hydrochloride and tartrazine (2)
- the content of ambroxol hydrochloride used in the present invention is preferably 0.1 to 5% by mass with respect to the total amount of the liquid, and is 0.2 to 1% by mass from the dosage of ambroxol hydrochloride and the flavor of the preparation. % Is more preferable.
- the tartrazine used in the present invention refers to a pigment usually used in foods and pharmaceuticals, yellow No. 4 in Japan, FD & C Yellow No. in the United States. 5. EU is authorized as E102.
- the amount of tartrazine used in the present invention is preferably 0.0001 to 0.1 parts by mass, and 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 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 each component is taken and dissolved with an appropriate amount of purified water, the pH is adjusted, the remaining purified water is added to adjust the volume, and filtration is performed as necessary.
- 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 60 mg of ambroxol hydrochloride, 0.083 mg of tartrazine, 4500 mg of 70% sorbitol solution, 15 mg of citric acid, 20 mg of sodium benzoate are dissolved in purified water. Thus, a clear internal solution was obtained (Table 1).
- Test example 1 (visual observation) Test solutions of Examples 1 to 4 and Comparative Examples 1 and 2 were prepared and observed visually. Table 2 shows the state of precipitation after each preparation.
- Test example 2 (light stability test) The test solutions obtained in Examples 1 to 4 and Comparative Examples 3 to 5 were exposed to 3000 Lux ⁇ 600 hours under a D65 light source. The colors of these test solutions were visually observed. The results are shown in Table 3.
- Examples 1 to 4 were in the yellow category even after phototransformation (after exposure to 3000 Lux ⁇ 600 hours under the D65 light source), and the color change was small even when compared with Comparative Examples 3 to 5. From this result, it became clear that the color change of the liquid agent can be suppressed by adding tartrazine.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pulmonology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Emergency Medicine (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
An internal liquid agent containing ambroxol hydrochloride and tartrazine is a stable ambroxol hydrochloride-containing liquid agent such that change in appearance due to coloring caused by irradiation of light is suppressed and such that precipitate is not formed.
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を含有する去痰薬は、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。
An expectorant containing ambroxol hydrochloride is widely accepted as a liquid for internal use and a syrup for children from the viewpoint of ease of taking.
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（サンセットイエローＦＣＦ）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）。
Moreover, about the pigment | dye used for coloring a formulation, when ambroxol hydrochloride and yellow No. 5 (sunset yellow FCF) are mix | blended simultaneously, it is known that a precipitation will be produced | generated (nonpatent literature 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、特定の色素であるタートラジンが塩酸アンブロキソールの光照射による色変化を抑制し、且つ沈殿を生成せずに安定的に液剤に配合できることを発見し、本発明を完成するに至った。
As a result of intensive studies to solve the above problems, the present inventors have determined that tartrazine, which is a specific pigment, suppresses color change due to light irradiation of ambroxol hydrochloride, and can be stably used as a liquid without forming a precipitate. It discovered that it could mix | blend and came to complete this invention.
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及びタートラジンを含有することを特徴とする内服液剤。
（２）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）に記載の内服液剤。
（３）タートラジン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）又は（２）に記載の内服液剤。 That is, the present invention includes the following.
(1) An internal liquid preparation containing ambroxol hydrochloride and tartrazine.
(2) The internal use liquid preparation according to (1), wherein the content of ambroxol hydrochloride is 0.1 to 5% by mass with respect to the total amount of the liquid preparation.
(3) The internal liquid preparation according to (1) or (2), wherein the content of tartrazine is 0.0001 to 0.1 parts by mass with respect to 1 part by mass of ambroxol hydrochloride.
（１）塩酸アンブロキソール及びタートラジンを含有することを特徴とする内服液剤。
（２）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）に記載の内服液剤。
（３）タートラジン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）又は（２）に記載の内服液剤。 That is, the present invention includes the following.
(1) An internal liquid preparation containing ambroxol hydrochloride and tartrazine.
(2) The internal use liquid preparation according to (1), wherein the content of ambroxol hydrochloride is 0.1 to 5% by mass with respect to the total amount of the liquid preparation.
(3) The internal liquid preparation according to (1) or (2), wherein the content of tartrazine is 0.0001 to 0.1 parts by mass with respect to 1 part by mass of ambroxol hydrochloride.
本発明により、塩酸アンブロキソール含有液剤に安定して色素を配合し、色変化を抑制した内服液剤を提供することが可能になった。
According to the present invention, it has become possible to provide an internal use liquid preparation in which a dye is stably blended with an ambroxol hydrochloride-containing liquid preparation and color change is suppressed.
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、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％がより好ましい。
The content of ambroxol hydrochloride used in the present invention is preferably 0.1 to 5% by mass with respect to the total amount of the liquid, and is 0.2 to 1% by mass from the dosage of ambroxol hydrochloride and the flavor of the preparation. % Is more preferable.
本発明に用いるタートラジンは、通常食品や医薬品に用いられる色素を指し、日本では黄色４号、アメリカではＦＤ＆Ｃ Ｙｅｌｌｏｗ Ｎｏ．５、ＥＵではＥ１０２として認可されているものである。本発明に用いるタートラジンの配合量は、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 tartrazine used in the present invention refers to a pigment usually used in foods and pharmaceuticals, yellow No. 4 in Japan, FD & C Yellow No. in the United States. 5. EU is authorized as E102. The amount of tartrazine used in the present invention is preferably 0.0001 to 0.1 parts by mass, and 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調整剤を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、各成分をとり適量の精製水で溶解した後、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 each component is taken and dissolved with an appropriate amount of purified water, the pH is adjusted, the remaining purified water is added to adjust the volume, and filtration is performed as necessary.
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。
実 施 Examples, comparative examples and test examples are given below to explain the present invention in more detail.
実施例１
塩酸アンブロキソール６０ｍｇ、タートラジン０．０８３ｍｇ、ソルビトール７０％溶液４５００ｍｇ、クエン酸１５ｍｇ、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（表１）。 Example 1
60 mg of ambroxol hydrochloride, 0.083 mg of tartrazine, 4500 mg of 70% sorbitol solution, 15 mg of citric acid, 20 mg of sodium benzoate are dissolved in purified water. Thus, a clear internal solution was obtained (Table 1).
塩酸アンブロキソール６０ｍｇ、タートラジン０．０８３ｍｇ、ソルビトール７０％溶液４５００ｍｇ、クエン酸１５ｍｇ、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（表１）。 Example 1
60 mg of ambroxol hydrochloride, 0.083 mg of tartrazine, 4500 mg of 70% sorbitol solution, 15 mg of citric acid, 20 mg of sodium benzoate are dissolved in purified water. Thus, a clear internal solution was obtained (Table 1).
以下の実施例２～４、比較例１～５も実施例１と同様に調製した。
The following Examples 2 to 4 and Comparative Examples 1 to 5 were also prepared in the same manner as Example 1.
試験例１（目視観察）
実施例１～４、比較例１～２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に示す。 Test example 1 (visual observation)
Test solutions of Examples 1 to 4 and Comparative Examples 1 and 2 were prepared and observed visually. Table 2 shows the state of precipitation after each preparation.
実施例１～４、比較例１～２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に示す。 Test example 1 (visual observation)
Test solutions of Examples 1 to 4 and Comparative Examples 1 and 2 were prepared and observed visually. Table 2 shows the state of precipitation after each preparation.
表２から明らかなように、タートラジンを配合した実施例１～４は、色素としてサンセットイエローＦＣＦを配合した比較例１及びアルラレッドＡＣを配合した比較例２と比較して沈殿の析出は見られず、性状安定性は良好であった。この結果から塩酸アンブロキソール配合内服液剤にタートラジンの配合が可能であることが明らかとなった。
As is apparent from Table 2, in Examples 1 to 4 in which tartrazine was blended, precipitation of precipitates was observed as compared with Comparative Example 1 in which Sunset Yellow FCF was blended as a pigment and Comparative Example 2 in which Alla Red AC was blended. The property stability was good. From this result, it became clear that tartrazine can be added to the internal use solution containing ambroxol hydrochloride.
試験例２（光安定性試験）
実施例１～４、比較例３～５で得た試験液をＤ６５光源下で３０００Ｌｕｘ×６００時間曝光させた。これらの試験液の色を目視で観察した。結果を表３に示す。 Test example 2 (light stability test)
The test solutions obtained in Examples 1 to 4 and Comparative Examples 3 to 5 were exposed to 3000 Lux × 600 hours under a D65 light source. The colors of these test solutions were visually observed. The results are shown in Table 3.
実施例１～４、比較例３～５で得た試験液をＤ６５光源下で３０００Ｌｕｘ×６００時間曝光させた。これらの試験液の色を目視で観察した。結果を表３に示す。 Test example 2 (light stability test)
The test solutions obtained in Examples 1 to 4 and Comparative Examples 3 to 5 were exposed to 3000 Lux × 600 hours under a D65 light source. The colors of these test solutions were visually observed. The results are shown in Table 3.
表３から、実施例１～４は光経変後（Ｄ６５光源下３０００Ｌｕｘ×６００時間曝光後）も黄色の範疇であり、比較例３～５と比較しても色の変化も小さかった。この結果からタートラジンを配合することで液剤の色変化を抑制できることが明らかとなった。
From Table 3, Examples 1 to 4 were in the yellow category even after phototransformation (after exposure to 3000 Lux × 600 hours under the D65 light source), and the color change was small even when compared with Comparative Examples 3 to 5. From this result, it became clear that the color change of the liquid agent can be suppressed by adding tartrazine.
本発明により、光照射による色の変化を抑制し、且つ色素沈殿が生じない安定な塩酸アンブロキソール含有内服液剤を提供することが可能となった。
According to the present invention, it has become possible to provide a stable ambroxol hydrochloride-containing liquid solution that suppresses color change due to light irradiation and does not cause pigment precipitation.
Claims (3)
- 塩酸アンブロキソール及びタートラジンを含有することを特徴とする内服液剤。 An oral solution characterized by containing ambroxol hydrochloride and tartrazine.
- 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％である請求項１に記載の内服液剤。 The internal liquid preparation according to claim 1, wherein the content of ambroxol hydrochloride is 0.1 to 5% by mass relative to the total amount of the liquid preparation.
- タートラジン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質量部である請求項１又は２に記載の内服液剤。 The internal liquid preparation according to claim 1 or 2, wherein the content of tartrazine is 0.0001 to 0.1 parts by mass with respect to 1 part by mass of ambroxol hydrochloride.
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| PH12016501528A PH12016501528B1 (en) | 2014-02-18 | 2016-08-03 | Internal liquid agent |
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| 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 |
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2015
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Patent Citations (2)
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| IYAKUHIN INTERVIEW FORM CYPROHEPTADINE ENSAN'EN SYRUP 0.04% 'TAIYO, April 2012 (2012-04-01), pages 4 - 6 * |
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| PH12016501528B1 (en) | 2017-02-06 |
| JPWO2015125754A1 (en) | 2017-03-30 |
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