JPWO2014013928A1 - Stabilized solid preparation for internal use - Google Patents
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- JPWO2014013928A1 JPWO2014013928A1 JP2014525799A JP2014525799A JPWO2014013928A1 JP WO2014013928 A1 JPWO2014013928 A1 JP WO2014013928A1 JP 2014525799 A JP2014525799 A JP 2014525799A JP 2014525799 A JP2014525799 A JP 2014525799A JP WO2014013928 A1 JPWO2014013928 A1 JP WO2014013928A1
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- ambroxol hydrochloride
- solid preparation
- carbocysteine
- mass
- acetaminophen
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- 238000002360 preparation method Methods 0.000 title claims abstract description 51
- 239000007787 solid Substances 0.000 title claims abstract description 42
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims abstract description 66
- 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 62
- 229960000985 ambroxol hydrochloride Drugs 0.000 claims abstract description 62
- GBFLZEXEOZUWRN-VKHMYHEASA-N S-carboxymethyl-L-cysteine Chemical compound OC(=O)[C@@H](N)CSCC(O)=O GBFLZEXEOZUWRN-VKHMYHEASA-N 0.000 claims abstract description 40
- 229960005489 paracetamol Drugs 0.000 claims abstract description 33
- 239000008187 granular material Substances 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 230000000087 stabilizing effect Effects 0.000 claims description 2
- 230000015556 catabolic process Effects 0.000 abstract description 4
- 238000006731 degradation reaction Methods 0.000 abstract description 4
- 238000010348 incorporation Methods 0.000 abstract 1
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- 230000036962 time dependent Effects 0.000 abstract 1
- 238000005469 granulation Methods 0.000 description 9
- 230000003179 granulation Effects 0.000 description 9
- 238000000034 method Methods 0.000 description 8
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- 239000001913 cellulose Substances 0.000 description 6
- 229920002678 cellulose Polymers 0.000 description 6
- 230000003419 expectorant effect Effects 0.000 description 6
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- 239000004480 active ingredient Substances 0.000 description 5
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
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- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 239000000820 nonprescription drug Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 230000000954 anitussive effect Effects 0.000 description 3
- 239000003434 antitussive agent Substances 0.000 description 3
- 229940124584 antitussives Drugs 0.000 description 3
- 229940046978 chlorpheniramine maleate Drugs 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
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- 235000012239 silicon dioxide Nutrition 0.000 description 3
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229940125715 antihistaminic agent Drugs 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- -1 caffeine anhydride) Chemical compound 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
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- 239000004615 ingredient Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 210000003097 mucus Anatomy 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229960002477 riboflavin Drugs 0.000 description 2
- 235000019192 riboflavin Nutrition 0.000 description 2
- 239000002151 riboflavin Substances 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 206010062717 Increased upper airway secretion Diseases 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- NTCYWJCEOILKNG-ROLPUNSJSA-N [(1r,2s)-1-hydroxy-1-phenylpropan-2-yl]-dimethylazanium;chloride Chemical compound Cl.CN(C)[C@@H](C)[C@H](O)C1=CC=CC=C1 NTCYWJCEOILKNG-ROLPUNSJSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000003907 antipyretic analgesic agent Substances 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000000168 bronchodilator agent Substances 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960000456 carbinoxamine maleate Drugs 0.000 description 1
- GVNWHCVWDRNXAZ-BTJKTKAUSA-N carbinoxamine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(OCCN(C)C)C1=CC=C(Cl)C=C1 GVNWHCVWDRNXAZ-BTJKTKAUSA-N 0.000 description 1
- 229960004399 carbocisteine Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940124579 cold medicine Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229960000920 dihydrocodeine Drugs 0.000 description 1
- RBOXVHNMENFORY-DNJOTXNNSA-N dihydrocodeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC RBOXVHNMENFORY-DNJOTXNNSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000001050 lubricating effect Effects 0.000 description 1
- 229940051020 methylephedrine hydrochloride Drugs 0.000 description 1
- 230000000510 mucolytic effect Effects 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 208000026435 phlegm Diseases 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- RYYVLZVUVIJVGH-UHFFFAOYSA-N trimethylxanthine Natural products CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
-
- 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
- A61P11/12—Mucolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Animal Behavior & Ethology (AREA)
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- Communicable Diseases (AREA)
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Abstract
アンブロキソール塩酸塩、Ｌ−カルボシステイン及びアセトアミノフェンを同時配合し、かつこれらを共存させたことを特徴とする内服用固形製剤は、Ｌ−カルボシステインによるアンブロキソール塩酸塩の経時的分解が顕著に抑制され、両成分の薬効が十分に発揮される、製品価値の高い内服用固形製剤である。A solid preparation for internal use characterized by the simultaneous incorporation of ambroxol hydrochloride, L-carbocysteine and acetaminophen, and coexistence thereof, is the time-dependent degradation of ambroxol hydrochloride by L-carbocysteine. Is a solid preparation for internal use with a high product value in which the pharmacological effects of both components are sufficiently exerted.
Description
本発明は、アンブロキソール塩酸塩の安定性を向上した内服用固形製剤に関する。 The present invention relates to a solid preparation for internal use with improved stability of ambroxol hydrochloride.
一般用医薬品（ＯＴＣ）の分野においては、如何に効果的にかぜの諸症状を除去等するかが薬剤開発において重要である。かぜ症候群のうち、特に痰の喀出（去痰）を図ることは、患者の負担が軽減されるため大変重要である。
アンブロキソール塩酸塩は、気道粘膜潤滑作用及び粘液溶解作用を有し、優れた去痰作用を有する化合物として広く知られている薬物である。また、Ｌ−カルボシステインは気道粘液調整及び粘膜正常化作用を有し、優れた去痰作用を有する化合物として広く知られている薬物である。これらの薬物は異なる去痰作用を有するため併用することは有用である。従来、去痰作用を増強させるとしてアンブロキソール塩酸塩とＬ−カルボシステインと粘液分泌促進作用を有する生薬を組み合わせて痰の喀出（去痰）を容易にすることが知られている（特許文献１）。In the field of over-the-counter medicines (OTC), how to effectively remove various symptoms of cold is important in drug development. Among cold syndromes, it is very important to eliminate sputum, especially because it reduces the burden on the patient.
Ambroxol hydrochloride is a drug widely known as a compound having airway mucosal lubricating action and mucolytic action and having excellent expectorant action. In addition, L-carbocysteine is a drug widely known as a compound having an airway mucus adjustment and a mucosa normalizing action and an excellent expectorant action. These drugs are useful because they have different expectorant effects. Conventionally, it is known to facilitate phlegm excretion (powder) by combining ambroxol hydrochloride, L-carbocysteine, and a herbal medicine having a mucus secretion promoting action to enhance expectorant action (Patent Document 1). .
本発明者らは、かぜ薬や鎮咳薬に汎用される、抗ヒスタミン剤、鎮咳剤などとともに、去痰剤としてアンブロキソール塩酸塩、Ｌ−カルボシステインを有効成分として配合し、さらに内服用固形製剤に汎用される添加剤を配合して製剤を製造したところ、アンブロキソール塩酸塩の含量が経時的に低下するという驚くべき知見を得た。さらに研究を進めた結果、意外にもアンブロキソール塩酸塩は、同じ去痰剤であるＬ−カルボシステインと配合禁忌であることを見出した。 In addition to antihistamines and antitussives, which are commonly used for cold medicines and antitussives, the present inventors formulated ambroxol hydrochloride and L-carbocysteine as active ingredients as active ingredients, and are further widely used for solid preparations for internal use. When the preparation was prepared by adding the additive, a surprising finding that the content of ambroxol hydrochloride decreased with time was obtained. As a result of further research, it was surprisingly found that ambroxol hydrochloride is contraindicated with L-carbocysteine, which is the same expectorant.
本発明は、アンブロキソール塩酸塩とＬ−カルボシステインを同時に配合しても、アンブロキソール塩酸塩の経時的分解が顕著に抑制された内服用固形製剤を提供することにある。また、本発明のさらに他の目的は、アンブロキソール塩酸塩とＬ−カルボシステインを同時配合かつ共存した状態にあるにも拘わらず、アンブロキソール塩酸塩が安定化された内服用固形製剤の製造方法を提供することにある。 An object of the present invention is to provide a solid preparation for internal use in which, even if ambroxol hydrochloride and L-carbocysteine are blended at the same time, degradation over time of ambroxol hydrochloride is remarkably suppressed. Yet another object of the present invention is to provide a solid preparation for internal use in which ambroxol hydrochloride is stabilized despite the fact that ambroxol hydrochloride and L-carbocysteine are co-formulated and coexist. It is to provide a manufacturing method.
そこで、本発明者らが鋭意検討した結果、上記目的を達成するためにアンブロキソール塩酸塩とＬ−カルボシステインを同時配合し、かつ共存させた内服用固形製剤であっても、これにアセトアミノフェンを配合することにより意外にもアンブロキソール塩酸塩の安定化が著しく図れることを見出した。 Therefore, as a result of intensive studies by the present inventors, even in the case of a solid preparation for internal use in which ambroxol hydrochloride and L-carbocysteine were simultaneously blended and coexisted in order to achieve the above-mentioned purpose, aceto It was surprisingly found that ambroxol hydrochloride can be remarkably stabilized by adding aminophen.
すなわち、本発明は
（１） アンブロキソール塩酸塩、Ｌ−カルボシステイン及びアセトアミノフェンを同時配合し、かつこれらを共存させたことを特徴とする内服用固形製剤、
（２） アンブロキソール塩酸塩、Ｌ−カルボシステイン及びアセトアミノフェンの合計が５５質量％を占める、（１）に記載の内服用固形製剤、
（３） 製剤中のアンブロキソール塩酸塩とＬ−カルボシステインの質量比が、１：１０〜１：４０である（１）に記載の内服用固形製剤、
（４） 製剤中のアンブロキソール塩酸塩とアセトアミノフェンの質量比が、１：５〜１：５０である（１）に記載の内服用固形製剤、
（５） １回服用量当たりの用量が１ｇ以下である、（１）に記載の内服用固形製剤、
（６） アンブロキソール塩酸塩、Ｌ−カルボシステイン及びアセトアミノフェンを含有する内服用固形製剤において、アンブロキソール塩酸塩、Ｌ−カルボシステイン及びアセトアミノフェンを同時配合かつ共存させた混合物を造粒して製造することを特徴とする、内服用固形製剤の製造方法、
（７） アンブロキソール塩酸塩及びＬ−カルボシステインを含み、アンブロキソール塩酸塩が安定化された内服用固形製剤を製造するための、アセトアミノフェンの使用、
（８） アンブロキソール塩酸塩及びＬ−カルボシステインを含む内服用固形製剤中のアンブロキソール塩酸塩を安定化するための、アセトアミノフェンの使用、
（９） アンブロキソール塩酸塩及びＬ−カルボシステインを含む内服用固形製剤の１回服用量当たりの用量を低減するための、アセトアミノフェンの使用、
である。That is, the present invention is (1) a solid preparation for internal use, characterized in that ambroxol hydrochloride, L-carbocysteine and acetaminophen are blended simultaneously,
(2) A solid preparation for internal use according to (1), wherein the total of ambroxol hydrochloride, L-carbocysteine and acetaminophen accounts for 55% by mass,
(3) The solid preparation for internal use according to (1), wherein the mass ratio of ambroxol hydrochloride and L-carbocysteine in the preparation is 1:10 to 1:40,
(4) The solid preparation for internal use according to (1), wherein the mass ratio of ambroxol hydrochloride and acetaminophen in the preparation is 1: 5 to 1:50,
(5) The solid preparation for internal use according to (1), wherein the dose per dose is 1 g or less,
(6) In a solid preparation for internal use containing ambroxol hydrochloride, L-carbocysteine and acetaminophen, a mixture containing ambroxol hydrochloride, L-carbocysteine and acetaminophen was simultaneously blended and coexisted. A method for producing a solid preparation for internal use, characterized by being produced by granulation,
(7) Use of acetaminophen for producing a solid preparation for internal use containing ambroxol hydrochloride and L-carbocysteine and stabilized with ambroxol hydrochloride,
(8) Use of acetaminophen for stabilizing ambroxol hydrochloride in an internal solid preparation containing ambroxol hydrochloride and L-carbocysteine,
(9) Use of acetaminophen to reduce the dose per single dose of an internal solid preparation containing ambroxol hydrochloride and L-carbocysteine,
It is.
本発明により、アンブロキソール塩酸塩の経時的分解を顕著に抑制し、製品価値の高い内服用固形製剤が得られる。
本発明の内服用固形製剤は、通常配合禁忌の成分同士を配合する際に選択される別顆粒法やフィルムコーティング操作等の煩雑な製造工程を必要とせず、アンブロキソール塩酸塩の安定性を備えた内服用固形製剤を簡便な方法で製造することができる。
本発明の「同時配合し、かつこれらを共存させた」とは、アンブロキソール塩酸塩、Ｌ−カルボシステイン及びアセトアミノフェンの３種を含み、これらが物理的／又は化学的に隔離されることなく混在している状態のことである。ただし、アンブロキソール塩酸塩、Ｌ−カルボシステイン及びアセトアミノフェン以外の成分の配合を排除するものではなく、３種の合計量に対して４５質量％未満の量であれば、他の成分の共存は許容される。 また、本発明は配合禁忌成分を安定に配合するための別顆粒法やフィルムコーティング操作などを必要としないため、これら操作に必要な賦形剤を使用する必要がない。そのため、本願発明の製剤は、製剤を小型化することができる。アンブロキソール塩酸塩及びＬ−カルボシステインによる去痰作用、及びアセトアミノフェンによる解熱鎮痛作用を兼ね備えた一般用医薬品（ＯＴＣ）製剤であっても、１回服用量当たりの用量を１ｇ以下に抑えた内服用固形製剤の提供が可能となった。According to the present invention, a solid preparation for internal use having a high product value can be obtained by remarkably suppressing the temporal degradation of ambroxol hydrochloride.
The solid preparation for internal use of the present invention does not require a complicated production process such as a separate granule method or film coating operation, which is usually selected when ingredients incompatible with each other are blended, and improves the stability of ambroxol hydrochloride. The solid preparation for internal use provided can be produced by a simple method.
The term “co-formulated and co-existing” in the present invention includes three types of ambroxol hydrochloride, L-carbocysteine and acetaminophen, which are physically / chemically isolated. It is a state where they are mixed together. However, it does not exclude the blending of components other than ambroxol hydrochloride, L-carbocysteine and acetaminophen, and if the amount is less than 45% by mass relative to the total amount of the three types, Coexistence is allowed. Further, since the present invention does not require a separate granule method or film coating operation for stably blending incompatible ingredients, it is not necessary to use excipients necessary for these operations. Therefore, the formulation of the present invention can reduce the size of the formulation. Even in the over-the-counter medicine (OTC) formulation that has an expectorant action by ambroxol hydrochloride and L-carbocysteine and an antipyretic analgesic action by acetaminophen, the dose per dose was suppressed to 1 g or less. It became possible to provide solid preparations for internal use.
本発明の内服用固形製剤中におけるアンブロキソール塩酸塩の含有量は、その薬効を示す量であれば特に限定されるものではないが、通常０．５〜１０質量％、好ましくは１．０〜３．０質量％である。 The content of ambroxol hydrochloride in the solid preparation for internal use of the present invention is not particularly limited as long as it shows the medicinal effect, but is usually 0.5 to 10% by mass, preferably 1.0. It is -3.0 mass%.
本発明の内服用固形製剤中におけるＬ−カルボシステインの含有量は、その薬効を示す量であれば特に限定されるものではないが、通常１０〜７０重量％、特に２０〜６０質量％が好ましい。また、アンブロキソール塩酸塩とＬ−カルボシステインの配合比（質量比）は、１：１０〜１：４０、特に１：１５〜１：３５が好ましい。 The content of L-carbocysteine in the solid preparation for internal use of the present invention is not particularly limited as long as it is an amount showing its medicinal effect, but it is usually preferably 10 to 70% by weight, particularly preferably 20 to 60% by weight. . Moreover, the compounding ratio (mass ratio) of ambroxol hydrochloride and L-carbocysteine is preferably 1:10 to 1:40, particularly 1:15 to 1:35.
本発明の内服用固形製剤中におけるアセトアミノフェンの含有量は、その薬効を示す量であれば特に限定されるものではないが、通常１０〜８５質量％、好ましくは２０〜６０質量％である。また、アンブロキソール塩酸塩とアセトアミノフェンの配合比（質量比）は通常１：５〜１：５０、アンブロキソール塩酸塩の安定性向上効果の点から特に１：１０〜１：３５が好ましい。また、Ｌ−カルボシステイン１質量部に対してアセトアミノフェンを０．２質量部以上が含有するのが好ましいが、アンブロキソール塩酸塩の安定性向上効果の点から０．６質量部以上含有するのが最も好ましい。本発明の内服用固形製剤中におけるアンブロキソール塩酸塩、カルボシステイン及びアセトアミノフェンの合計量は、３０質量％以上、好ましくは５０〜９５質量％である。 The content of acetaminophen in the solid preparation for internal use of the present invention is not particularly limited as long as it shows the medicinal effect, but is usually 10 to 85% by mass, preferably 20 to 60% by mass. . The mixing ratio (mass ratio) of ambroxol hydrochloride and acetaminophen is usually from 1: 5 to 1:50, and particularly from 1:10 to 1:35 in terms of the effect of improving the stability of ambroxol hydrochloride. preferable. Moreover, it is preferable that 0.2 mass part or more of acetaminophen is contained with respect to 1 mass part of L-carbocysteine, but 0.6 mass part or more is contained from the point of the stability improvement effect of ambroxol hydrochloride Most preferably. The total amount of ambroxol hydrochloride, carbocysteine and acetaminophen in the solid preparation for internal use of the present invention is 30% by mass or more, preferably 50 to 95% by mass.
また、本発明の内服用固形製剤中にはアンブロキソール塩酸塩、Ｌ−カルボシステイン、アセトアミノフェンの他に、本発明の効果を損なわない質的、量的範囲で、通常用いられる他の有効成分（例えばジヒドロコデインリン酸塩等の鎮咳剤、クロルフェニラミンマレイン酸塩、カルビノキサミンマレイン酸塩等の抗ヒスタミン剤、メチルエフェドリン塩酸塩等の気管支拡張剤、カフェイン無水物等の中枢興奮剤など）、賦形剤、崩壊剤、結合剤などを配合しうる。 Further, in the solid preparation for internal use of the present invention, in addition to ambroxol hydrochloride, L-carbocysteine, and acetaminophen, other qualitative and quantitative ranges that do not impair the effects of the present invention are used. Active ingredients (eg antitussives such as dihydrocodeine phosphate, antihistamines such as chlorpheniramine maleate and carbinoxamine maleate, bronchodilators such as methylephedrine hydrochloride, central stimulants such as caffeine anhydride) , Excipients, disintegrants, binders and the like may be incorporated.
本発明の内服用固形製剤の剤形は、特に限定されず、散剤、細粒剤、顆粒剤、丸剤、錠剤（フィルムコーティング錠、糖衣錠、積層錠を含む）、カプセル剤等の剤形を包含する。それぞれ必要に応じて有効成分、賦形剤、結合剤、崩壊剤、フィルムコーティング剤、滑沢剤、抗酸化剤、香料、および着色剤等の慣用の製剤添加剤を適当量配合しても良い。 The dosage form of the solid preparation for internal use of the present invention is not particularly limited, and dosage forms such as powders, fine granules, granules, pills, tablets (including film-coated tablets, sugar-coated tablets, laminated tablets), capsules, etc. Include. If necessary, an appropriate amount of conventional formulation additives such as active ingredients, excipients, binders, disintegrants, film coating agents, lubricants, antioxidants, fragrances, and coloring agents may be blended. .
本発明の内服用固形製剤は、常法により製造することができ、その方法は特に限定されるものではない。造粒方法は特に限定されず、その剤形に応じて、任意の慣用の方法例えば攪拌造粒、流動層造粒、押し出し造粒、転動流動造粒、乾式造粒などの方法により造粒して製造する。これらは一般的な製剤機器を用いて一般的な方法で製剤化を行うことができる。上記のように造粒した後、造粒物を被覆しても良い。また、その造粒物に適宜上記有効成分や賦形剤などの慣用の製剤添加剤を配合してもよく、また、このようにして得た混合物を打錠して錠剤とすることもできる。造粒物を用いて市販の積層錠剤機により２層以上の多層錠の錠剤としてもよい。 The solid preparation for internal use of the present invention can be produced by a conventional method, and the method is not particularly limited. The granulation method is not particularly limited, and depending on the dosage form, granulation is performed by any conventional method such as stirring granulation, fluidized bed granulation, extrusion granulation, rolling fluid granulation, dry granulation, etc. To manufacture. These can be formulated by a general method using a general pharmaceutical device. After granulation as described above, the granulated product may be coated. In addition, conventional granule additives such as the above active ingredients and excipients may be appropriately blended with the granulated product, and the mixture thus obtained can be tableted into tablets. It is good also as a tablet of a multilayer tablet of two or more layers using a granulation thing with a commercially available laminated tablet machine.
以下、実施例、比較例及び試験例を挙げて、本発明を更に詳細に説明する。 Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples, and Test Examples.
（対照例１）
アンブロキソール塩酸塩１．６質量％、クロルフェニラミンマレイン酸塩０．３質量％、リボフラビン０．４質量％、アセトアミノフェン３１．８質量％、結晶セルロース３９．３質量％、Ｄ-マンニトール１２．４質量％、バレイショデンプン５．３質量％、ヒドロキシプロピルセルロース、６．４質量％、軽質無水ケイ酸１．７質量％、乳糖０．８質量％を混合して固形組成物を得、この固形組成物に精製水を添加して造粒し、１包あたり９４３．９ｍｇの顆粒剤を得た。(Control 1)
Ambroxol hydrochloride 1.6% by mass, chlorpheniramine maleate 0.3% by mass, riboflavin 0.4% by mass, acetaminophen 31.8% by mass, crystalline cellulose 39.3% by mass, D-mannitol 12.4% by mass, potato starch 5.3% by mass, hydroxypropylcellulose, 6.4% by mass, light anhydrous silicic acid 1.7% by mass, lactose 0.8% by mass to obtain a solid composition, Purified water was added to this solid composition and granulated to obtain 943.9 mg of granules per packet.
（対照例２）
対照例１のアセトアミノフェン３１．８質量％を結晶セルロースに置き換えて造粒し、１包あたり９４３．９ｍｇの顆粒剤を得た。(Control 2)
Granules were obtained by replacing 31.8% by mass of acetaminophen of Control Example 1 with crystalline cellulose to obtain 943.9 mg of granules per packet.
（実施例１）
アンブロキソール塩酸塩１．６質量％、L-カルボシステイン２６．５質量％、クロルフェニラミンマレイン酸塩０．３質量％、リボフラビン０．４質量％、アセトアミノフェン３１．８質量％、結晶セルロース１２．８質量％、Ｄ-マンニトール１２．４質量％、バレイショデンプン５．３質量％、ヒドロキシプロピルセルロース６．４質量％、軽質無水ケイ酸１．７質量％、乳糖０．８質量％を混合して固形組成物を得、この固形組成物に精製水を添加して造粒し、１包あたり９４３．９ｍｇの顆粒剤を得た。Example 1
Ambroxol hydrochloride 1.6% by mass, L-carbocysteine 26.5% by mass, chlorpheniramine maleate 0.3% by mass, riboflavin 0.4% by mass, acetaminophen 31.8% by mass, crystals Cellulose 12.8% by mass, D-mannitol 12.4% by mass, potato starch 5.3% by mass, hydroxypropylcellulose 6.4% by mass, light anhydrous silicic acid 1.7% by mass, lactose 0.8% by mass A solid composition was obtained by mixing, and purified water was added to the solid composition and granulated to obtain 943.9 mg of granules per packet.
（比較例１）
実施例１のアセトアミノフェン３１．８質量％を結晶セルロースに置き換えて造粒し、１包あたり９４３．９ｍｇの顆粒剤を得た。(Comparative Example 1)
Granules were obtained by replacing 31.8% by mass of acetaminophen of Example 1 with crystalline cellulose to obtain 943.9 mg of granules per packet.
試験例１
対照例１、２で製造した製剤を２５℃６０％ＲＨ下に２日間保存した後、６５℃−１週間保存し、アンブロキソール塩酸塩の残存率をＨＰＬＣ法により評価した。結果を表１に示す。数値は全て対直後％である。Test example 1
The preparations produced in Control Examples 1 and 2 were stored at 25 ° C. and 60% RH for 2 days and then stored at 65 ° C. for 1 week, and the residual ratio of ambroxol hydrochloride was evaluated by HPLC. The results are shown in Table 1. All figures are% immediately after.
試験例２
実施例１および比較例１で製造した製剤を２５℃６０％ＲＨ下に２日間保存した後、６５℃−１週間及び２週間保存し、アンブロキソール塩酸塩の残存率をＨＰＬＣ法により評価した。数値は全て対直後％である。Test example 2
The preparations produced in Example 1 and Comparative Example 1 were stored at 25 ° C. and 60% RH for 2 days, then stored at 65 ° C. for 1 week and 2 weeks, and the residual ratio of ambroxol hydrochloride was evaluated by HPLC method. . All figures are% immediately after.
表１〜２から明らかなように、アンブロキソール塩酸塩はＬ−カルボシステインの共存により安定性が低下することが分かった。Ｌ−カルボシステインの共存により低下したアンブロキソール塩酸塩の残存率は、アセトアミノフェンを配合することにより改善することがわかった。 As is clear from Tables 1 and 2, it was found that the stability of ambroxol hydrochloride was lowered by the coexistence of L-carbocysteine. It was found that the residual ratio of ambroxol hydrochloride decreased by the coexistence of L-carbocysteine was improved by adding acetaminophen.
（対照例３）
アンブロキソール塩酸塩１．６質量％、乳糖８１．６質量％、結晶セルロース９．１質量％、ヒドロキシプロピルセルロース、６．１質量％、軽質無水ケイ酸１．６質量％を混合して固形組成物を得、この固形組成物に精製水を添加して造粒し、１包あたり９８０．０ｍｇの顆粒剤を得た。(Control 3)
A solid mixture of 1.6% by mass of ambroxol hydrochloride, 81.6% by mass of lactose, 9.1% by mass of crystalline cellulose, 6.1% by mass of hydroxypropyl cellulose, and 1.6% by mass of light anhydrous silicic acid. A composition was obtained, and purified water was added to the solid composition and granulated to obtain 980.0 mg of granules per packet.
（実施例２）
アンブロキソール塩酸塩１．６質量％、L-カルボシステイン５１．０質量％、アセトアミノフェン３０．６質量％、結晶セルロース９．１質量％、ヒドロキシプロピルセルロース６．１質量％、軽質無水ケイ酸１．６質量％を混合して固形組成物を得、この固形組成物に精製水を添加して造粒し、１包あたり９８０．０ｍｇの顆粒剤を得た。(Example 2)
Ambroxol hydrochloride 1.6% by mass, L-carbocysteine 51.0% by mass, acetaminophen 30.6% by mass, crystalline cellulose 9.1% by mass, hydroxypropylcellulose 6.1% by mass, light anhydrous silica A solid composition was obtained by mixing 1.6% by mass of acid, and purified water was added to the solid composition and granulated to obtain 980.0 mg of granules per package.
（比較例２）
実施例２のアセトアミノフェン３０．６質量％を乳糖に置き換えて造粒し、１包あたり９８０．０ｍｇの顆粒剤を得た。(Comparative Example 2)
Granules were obtained by replacing 30.6% by mass of acetaminophen in Example 2 with lactose to obtain 980.0 mg of granules per packet.
試験例３
対照例３で製造した製剤を２５℃６０％ＲＨ下に２日間保存した後、６５℃−２週間保存し、アンブロキソール塩酸塩の残存率をＨＰＬＣ法により評価した。結果を表３に示す。数値は全て対直後％である。Test example 3
The preparation produced in Control Example 3 was stored at 25 ° C. and 60% RH for 2 days, and then stored at 65 ° C. for 2 weeks, and the residual ratio of ambroxol hydrochloride was evaluated by the HPLC method. The results are shown in Table 3. All figures are% immediately after.
試験例３
実施例２および比較例２で製造した製剤を２５℃６０％ＲＨ下に２日間保存した後、６５℃−１週間及び２週間保存し、アンブロキソール塩酸塩の残存率をＨＰＬＣ法により評価した。数値は全て対直後％である。Test example 3
The preparations produced in Example 2 and Comparative Example 2 were stored at 25 ° C. and 60% RH for 2 days, then stored at 65 ° C. for 1 week and 2 weeks, and the residual ratio of ambroxol hydrochloride was evaluated by HPLC method. . All figures are% immediately after.
表３〜４から明らかなように、アンブロキソール塩酸塩はＬ−カルボシステインの共存により安定性が低下することが分かった。Ｌ−カルボシステインの共存により低下したアンブロキソール塩酸塩の残存率は、アセトアミノフェンを配合することにより改善することがわかった。 As apparent from Tables 3 to 4, it was found that the stability of ambroxol hydrochloride was lowered by the coexistence of L-carbocysteine. It was found that the residual ratio of ambroxol hydrochloride decreased by the coexistence of L-carbocysteine was improved by adding acetaminophen.
本発明により、アンブロキソール塩酸塩とＬ−カルボシステインを同時に配合しても、アンブロキソール塩酸塩の経時的分解が顕著に抑制された内服用固形製剤を提供することが可能となる。また、１回服用量が少ない内服用固形製剤を提供することが可能となるので、患者のコンプライアンスを向上することができる。 According to the present invention, it is possible to provide a solid preparation for internal use in which degradation of ambroxol hydrochloride with time is remarkably suppressed even when ambroxol hydrochloride and L-carbocysteine are blended simultaneously. In addition, since it is possible to provide a solid preparation for internal use with a small single dose, patient compliance can be improved.
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| JPH08337532A (en) * | 1995-06-14 | 1996-12-24 | Takeda Chem Ind Ltd | Medicinal composition |
| JPH1045595A (en) * | 1996-05-22 | 1998-02-17 | Taisho Pharmaceut Co Ltd | Antitussive |
| JP2002363072A (en) * | 2001-04-03 | 2002-12-18 | Taisho Pharmaceut Co Ltd | Antitussive composition |
| JP2006104186A (en) * | 2004-09-10 | 2006-04-20 | Takeda Chem Ind Ltd | Pharmaceutical composition for common cold |
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| JPH08337532A (en) * | 1995-06-14 | 1996-12-24 | Takeda Chem Ind Ltd | Medicinal composition |
| JPH1045595A (en) * | 1996-05-22 | 1998-02-17 | Taisho Pharmaceut Co Ltd | Antitussive |
| JP2002363072A (en) * | 2001-04-03 | 2002-12-18 | Taisho Pharmaceut Co Ltd | Antitussive composition |
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