JP4959991B2 - Suspension pharmaceutical composition containing tranilast or a pharmacologically acceptable salt thereof - Google Patents
Suspension pharmaceutical composition containing tranilast or a pharmacologically acceptable salt thereof Download PDFInfo
- Publication number
- JP4959991B2 JP4959991B2 JP2006057048A JP2006057048A JP4959991B2 JP 4959991 B2 JP4959991 B2 JP 4959991B2 JP 2006057048 A JP2006057048 A JP 2006057048A JP 2006057048 A JP2006057048 A JP 2006057048A JP 4959991 B2 JP4959991 B2 JP 4959991B2
- Authority
- JP
- Japan
- Prior art keywords
- tranilast
- skin
- particle size
- menthol
- size distribution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- NZHGWWWHIYHZNX-CSKARUKUSA-N tranilast Chemical compound C1=C(OC)C(OC)=CC=C1\C=C\C(=O)NC1=CC=CC=C1C(O)=O NZHGWWWHIYHZNX-CSKARUKUSA-N 0.000 title claims description 114
- 229960005342 tranilast Drugs 0.000 title claims description 114
- 150000003839 salts Chemical class 0.000 title claims description 8
- 239000000725 suspension Substances 0.000 title claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 title description 5
- 239000002245 particle Substances 0.000 claims description 44
- 231100000245 skin permeability Toxicity 0.000 claims description 40
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims description 29
- 238000009826 distribution Methods 0.000 claims description 24
- 229940041616 menthol Drugs 0.000 claims description 20
- 239000004480 active ingredient Substances 0.000 claims description 10
- 239000002674 ointment Substances 0.000 claims description 9
- 239000007900 aqueous suspension Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 3
- 230000002708 enhancing effect Effects 0.000 claims description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims 2
- 230000000052 comparative effect Effects 0.000 description 33
- 238000012360 testing method Methods 0.000 description 29
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 28
- 210000003491 skin Anatomy 0.000 description 27
- 239000000843 powder Substances 0.000 description 23
- -1 fatty acid ester Chemical class 0.000 description 22
- 239000006071 cream Substances 0.000 description 20
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 15
- 230000001186 cumulative effect Effects 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 14
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- 230000000694 effects Effects 0.000 description 10
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 229940079593 drug Drugs 0.000 description 8
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- PRAKJMSDJKAYCZ-UHFFFAOYSA-N squalane Chemical compound CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 3
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- 229960000686 benzalkonium chloride Drugs 0.000 description 2
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 2
- 229960001950 benzethonium chloride Drugs 0.000 description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
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- 210000004207 dermis Anatomy 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
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- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
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- 229940039717 lanolin Drugs 0.000 description 2
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- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
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- 231100000241 scar Toxicity 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- JREYOWJEWZVAOR-UHFFFAOYSA-N triazanium;[3-methylbut-3-enoxy(oxido)phosphoryl] phosphate Chemical compound [NH4+].[NH4+].[NH4+].CC(=C)CCOP([O-])(=O)OP([O-])([O-])=O JREYOWJEWZVAOR-UHFFFAOYSA-N 0.000 description 2
- DUXYWXYOBMKGIN-UHFFFAOYSA-N trimyristin Chemical compound CCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCC DUXYWXYOBMKGIN-UHFFFAOYSA-N 0.000 description 2
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- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
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Description
本発明は、トラニラストまたはその薬理学的に許容される塩を活性成分として含有する外用医薬組成物に関するものである。 The present invention relates to an external pharmaceutical composition containing tranilast or a pharmacologically acceptable salt thereof as an active ingredient.
トラニラスト(3,4−ジメトキシシンナモイルアントラニル酸)は、肥満細胞、或いは各種炎症細胞からのケミカルメディエーターの遊離抑制作用を有し、ケロイド・肥厚性瘢痕の治療剤として有用であることが知られており、経口剤としてカプセル剤、錠剤、ドライシロップ剤、細粒剤といった製剤が医療の現場で用いられている。 Tranilast (3,4-dimethoxycinnamoyl anthranilic acid) has an inhibitory action on the release of chemical mediators from mast cells or various inflammatory cells, and is known to be useful as a therapeutic agent for keloid / hypertrophic scars. In addition, preparations such as capsules, tablets, dry syrups, and fine granules are used in the field of medicine as oral preparations.
しかしながら、トラニラストは難溶性物質であるために、吸収率が低いという特徴がある。このため例えば、体表面に生じるケロイド・肥厚性瘢痕を治療するために、トラニラストを経口剤として投与した場合には、有効血中薬物濃度を維持するために多量の薬物が投与される。多量のトラニラストは、患者に負担を与え、しばしば胃障害、肝障害といった副作用を発現することがある。このため、ケロイドなどに局所適用できる外用剤の開発・研究が望まれており、現在までに外用剤として種々の提案がなされている。 However, since tranilast is a poorly soluble substance, it has a feature of low absorption. Therefore, for example, when tranilast is administered as an oral preparation in order to treat keloid / hypertrophic scar generated on the body surface, a large amount of drug is administered in order to maintain an effective blood drug concentration. Large amounts of tranilast are burdensome to the patient and often have side effects such as gastric and liver damage. For this reason, development and research of external preparations that can be applied locally to keloids are desired, and various proposals have been made as external preparations to date.
例えば、支持体上に有効成分としてトラニラストを含有するアクリル系粘着剤層を設けたことを特徴とするトラニラスト経皮吸収貼付剤(特開2003−119132)、溶解補助剤により均一に溶解した状態で膏体基剤に含有した外用剤(特開2001−131064)トラニラストを塩基性水溶液に加温溶解した後、所望により、界面活性剤、懸濁化剤、安定化剤、防腐剤、その他の医薬品添加物を加え、軟膏基剤と練り合わせて軟膏とする方法(特開平6−128153号)等の提案がなされている。しかし、吸収助剤の脂肪酸エステル及びアルコール類の配合量が多いことや、吸収助剤として塩基性物質を使用するために皮膚刺激性が懸念されるといった問題点がある。更に、高濃度のトラニラスト製剤化の開発は困難となっている。 For example, a tranilast transdermal absorption patch (JP-A No. 2003-119132) characterized by providing an acrylic pressure-sensitive adhesive layer containing tranilast as an active ingredient on a support, in a state of being uniformly dissolved by a solubilizing agent An external preparation (JP-A-2001-131664) tranilast contained in a plaster base is dissolved in a basic aqueous solution by heating, and then a surfactant, a suspending agent, a stabilizer, an antiseptic, and other pharmaceuticals as required. There have been proposals such as a method of adding an additive and kneading with an ointment base to make an ointment (Japanese Patent Laid-Open No. 6-128153). However, there are problems that the blending amount of fatty acid ester and alcohol as an absorption aid is large, and skin irritation is a concern because a basic substance is used as an absorption aid. Furthermore, development of a high concentration tranilast formulation has become difficult.
本発明は、上記した課題に鑑みてなされたものであり、その目的は、トラニラストを有効成分とする新たな形態の製剤を提供するものであり、安全性が高く、皮膚からの有効成分の吸収性に極めて優れ、安定性が良好であり、且つ刺激性の少ないトラニラスト含有医薬組成物を提供することである。
トラニラストの皮膚からの吸収性を高めるには、トラニラストが分子型で存在するpH3〜7の領域にすることが好ましい。しかしながら、トラニラストが分子型で存在するということは、水に溶解しないということになる。発明者らは、このような問題点を解決すべく、鋭意検討を行った結果、トラニラストが分子型で存在するpH3〜7の領域では、水には溶解しないという特徴を逆に利用して、トラニラストの粒子径を超微細化し、水性懸濁剤とすることを見出した。更に、適当な透過促進剤を併用することにより、皮膚からのトラニラストの吸収性を飛躍的に高められることを見出し、基本的には本発明を完成するに至った。
In order to increase the absorption of tranilast from the skin, it is preferable to make the region of pH 3-7 where tranilast exists in a molecular form. However, the presence of tranilast in molecular form means that it does not dissolve in water. As a result of intensive investigations to solve such problems, the inventors have reversely utilized the feature that tranilast does not dissolve in water in the region of
こうして、第1の発明に係る水性懸濁液剤は、トラニラストまたはその薬理学的に許容される塩を有効成分とする粒子がpH3〜7の範囲で懸濁しており、かつ0.5質量%〜4質量%のメントールが含有されていることを特徴とする。
このとき、粒子の粒子径分布の中心が0.005μm〜5μm(より好ましくは、0.005μm〜2μm)の範囲にあり、粒子径分布の90%メジアン径が10μm以下であることが好ましい。
Thus, in the aqueous suspension according to the first invention, particles containing tranilast or a pharmacologically acceptable salt thereof as an active ingredient are suspended in a pH range of 3 to 7, and 0.5% by mass to It contains 4% by mass of menthol.
At this time, the center of the particle size distribution of the particles is preferably in the range of 0.005 μm to 5 μm (more preferably 0.005 μm to 2 μm), and the 90% median diameter of the particle size distribution is preferably 10 μm or less.
また、第2の発明に係るトラニラストの皮膚透過性を高める方法は、トラニラストまたはその薬理学的に許容される塩を有効成分とし、その粒子径分布の中心が0.005μm〜5μmであり、粒子径分布の90%メジアン径が10μm以下であり、pHが3〜7である懸濁物に、0.5質量%〜4質量%のメントールを添加させることを特徴とする。本発明においては、粒子径分布の中心が0.005μm〜2μmであることが好ましい。 The method for enhancing the skin permeability of tranilast according to the second invention comprises tranilast or a pharmacologically acceptable salt thereof as an active ingredient, the center of the particle size distribution is 0.005 μm to 5 μm, A menthol of 0.5 mass% to 4 mass% is added to a suspension having a 90% median diameter of a diameter distribution of 10 μm or less and a pH of 3 to 7. In the present invention, the center of the particle size distribution is preferably 0.005 μm to 2 μm.
本発明によれば、トラニラストを含有する剤をケロイドに直接塗布し、局所で治療することができるため、患者の安全性が高く、かつ皮膚からの有効成分の吸収性に極めて優れたトラニラスト含有医薬組成物を提供することができる。 According to the present invention, an agent containing tranilast can be applied directly to keloid and treated locally, so that the drug containing tranilast is highly safe for patients and has an excellent ability to absorb active ingredients from the skin. A composition can be provided.
次に、本発明を実施するための最良の形態について詳細に説明するが、本発明の技術的範囲は、下記実施形態又は実施例によって限定されるものではなく、その要旨を変更することなく、様々に改変して実施することができる。また、本発明の技術的範囲は、均等の範囲にまで及ぶものである。
本発明で使用されるトラニラストまたはその薬理学的に許容される塩は、pHが3〜7の範囲にある基剤に懸濁されており、トラニラストの粒子径分布の中心が0.005μm〜5μmであり、粒子径分布の90%メジアン径が10μm以下であることが好ましく、0.005μm〜2μmであり、粒子径分布の90%メジアン径は、10μm以下であることがより好ましい。上記粒子径分布の中心と、粒子径分布の90%メジアン径とに関する数値範囲に関しては、目的に応じて互いに矛盾しないものを任意に組み合わせて設定することができる。
Next, the best mode for carrying out the present invention will be described in detail, but the technical scope of the present invention is not limited by the following embodiments or examples, and without changing the gist thereof, Various modifications can be made. Further, the technical scope of the present invention extends to an equivalent range.
Tranilast or a pharmacologically acceptable salt thereof used in the present invention is suspended in a base having a pH in the range of 3 to 7, and the center of the particle size distribution of tranilast is 0.005 μm to 5 μm. The 90% median diameter of the particle size distribution is preferably 10 μm or less, more preferably 0.005 μm to 2 μm, and the 90% median diameter of the particle size distribution is more preferably 10 μm or less. The numerical range relating to the center of the particle size distribution and the 90% median size of the particle size distribution can be set in any combination according to the purpose.
トラニラストは、基剤のpHが3〜7の範囲(好ましくはpH4〜6.5、更に好ましくはpH5〜6の範囲)であれば、基剤に懸濁されている。しかし、基剤のpHが7より上がりアルカリ領域になると、トラニラストが見かけ上溶解し、溶解した溶液中のトラニラストは水による加水分解を受け分解しやすくなる。また、pHが3より下がると基剤の酸性度が強くなり、トラニラストではなく基剤による皮膚に対する刺激が大きくなるため好ましくない。
Tranilast is suspended in the base when the pH of the base is in the range of 3 to 7 (preferably
粉体の粒子径分布は一般的に横軸に粒子径の対数をとり、縦軸に頻度%をとるとき正規分布に近似したある広がりを持った分布を示す。このため、粒子径分布の中心が0.005μm〜5μmであったとしても、分布に広がりがあるために5μm以上の粒子を含むことになる。本発明では、この粒度分布の広がりに対し、トラニラストの粒子径分布の90%メジアン径が10μm以下であること(言いかえれば、10μmより大きな粒子径を示す粒子が全体に占める割合が、10%未満であること)が重要である。 The particle size distribution of a powder generally shows a distribution having a certain spread approximated to a normal distribution when the logarithm of the particle size is taken on the horizontal axis and the frequency% is taken on the vertical axis. For this reason, even if the center of the particle size distribution is 0.005 μm to 5 μm, the distribution is wide, so that particles of 5 μm or more are included. In the present invention, the 90% median diameter of the tranilast particle size distribution is 10 μm or less with respect to the spread of the particle size distribution (in other words, the proportion of particles having a particle size larger than 10 μm is 10% Is less important).
メントールは、市販のものを購入して使用できる。メントールの配合量は0.5質量%〜4質量%が好ましく、0.5質量%〜2質量%が更に好ましい。0.5質量%以下では、皮膚透過性が低く、また4質量%以上ではメントールの刺激感が強すぎて好ましくない。
本発明における水性懸濁液は、2次凝集を抑制する目的で、さらに界面活性剤及び/或いは水溶性高分子を加え、トラニラスト粒子のゼータ電位の絶対値を20mV〜150mVの範囲とすることにより、再分散性を良好にできる。ゼータ電位の調製に用いる界面活性剤の種類、水溶性高分子の種類、薬物の量は、pHによっても異なるが0.05%〜3%の範囲であることが好ましい。
Menthol can be purchased and used commercially. The blending amount of menthol is preferably 0.5% by mass to 4% by mass, and more preferably 0.5% by mass to 2% by mass. If it is 0.5% by mass or less, the skin permeability is low, and if it is 4% by mass or more, the menthol irritation is too strong.
In order to suppress secondary aggregation, the aqueous suspension in the present invention is further added with a surfactant and / or a water-soluble polymer, and the absolute value of the zeta potential of the tranilast particles is set in the range of 20 mV to 150 mV. The redispersibility can be improved. The type of surfactant, the type of water-soluble polymer, and the amount of drug used to adjust the zeta potential vary depending on the pH, but are preferably in the range of 0.05% to 3%.
界面活性剤としては、塩化ベンゼトニウム、塩化ベンザルコニウム等の4級アミン系界面活性剤やポリオキシエチレン高級アルコールエーテル類、ポリオキシエチレンソルビタン脂肪酸エステル類、グリセリン脂肪酸エステル類、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレン脂肪酸エステル、ポリオキシエチレンノニルフェニルエーテル、ポリオキシエチレンオクチルフェニルエーテル、ソルビタン脂肪酸エステル、プロピレングリコール脂肪酸エステル、脂肪酸ポリエチレングリコール、ポリグリセリン脂肪酸エステル、ショ糖脂肪酸エステル等の非イオン性界面活性剤類、などを挙げることができる。 Surfactants include quaternary amine surfactants such as benzethonium chloride and benzalkonium chloride, polyoxyethylene higher alcohol ethers, polyoxyethylene sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene hydrogenated castor oil , Polyoxyethylene fatty acid ester, polyoxyethylene nonyl phenyl ether, polyoxyethylene octyl phenyl ether, sorbitan fatty acid ester, propylene glycol fatty acid ester, fatty acid polyethylene glycol, polyglycerin fatty acid ester, sucrose fatty acid ester, etc. And the like.
水溶性高分子としては、メチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、カルボキシメチルセルロース、ポリビニルアルコール、ポリビニルピロリドン等を挙げることできる。
本発明におけるトラニラストの含有量は、特に制限はない。通常、0.5%〜10%の実際に使用されている製剤の含有量と同じ濃度であるが、更に高濃度のトラニラスト懸濁液を作り、使用濃度に合わせて希釈して製剤とする事も可能である。
また、さらに製剤学的に汎用されている賦形剤、基剤、安定剤、保存剤、pH調整剤、軟膏基剤等を添加し、軟膏剤、ローション剤等とすることができる。かかる製剤学的に汎用されている成分としては、例えば、以下のような成分を挙げることができる。
Examples of the water-soluble polymer include methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, and polyvinyl pyrrolidone.
The tranilast content in the present invention is not particularly limited. Usually, the concentration is 0.5% to 10%, which is the same as the content of the formulation actually used. However, a higher concentration tranilast suspension should be prepared and diluted to the concentration to be used. Is also possible.
Further, excipients, bases, stabilizers, preservatives, pH adjusters, ointment bases, and the like that are widely used in pharmacology can be added to obtain ointments, lotions, and the like. Examples of such components that are widely used in pharmacology include the following components.
基剤成分として、グリセリン、ブチレングリコール、ジプロピレングリコール、プロピレングリコール、エタノール、イソプロパノール、水、ソルビトール、マンニトール、キシリトール、ブドウ糖、イプシロンアミノカプロン酸、グリシン、グルタミン酸塩、ヒアルロン酸ナトリウム、ステアリン酸グリセリン、ポリエチレングリコール類、カルボキシビニルポリマー、ポリビニルピロリドン、ポリビニルアルコールやセチルアルコール、イソステアリルアルコール、ステアリルアルコール、ヘキシルデカノール、オクチルドデカノールなどのアルコール類、メチルポリシロキサン、メチルフェニルポリシロキサン、ドデカメチルポリシロキサン等のシリコーン油類、アボガド油、アルモンド油、オリーブ油、カカオ脂、牛脂、ゴマ油、小麦胚芽油、サフラワー油、タートル油、椿油、パーシック油、ひまし油、ブドウ油、マカデミアナッツ油、ミンク油、黄卵油、紅花油、モクロウ、ヤシ油、ローズヒップ油等の油脂類、オレンジラフィー油、ホホバ油等の液状蝋類、流動パラフィン、液状ワセリン、スクワラン、スクワレン等の液状炭化水素類、ラウリン酸、ミリスチン酸、オレイン酸等の高級脂肪酸、リノール酸エチル、ミリスチン酸イソプロピル、ラウリン酸ヘキシル、ミリスチン酸オクチルドデシル、オレイン酸デシル、オレイン酸オクチルドデシル、ジメチルオクタン酸ヘキシルデシル等の脂肪酸エステル類を挙げることができる。 Base ingredients include glycerin, butylene glycol, dipropylene glycol, propylene glycol, ethanol, isopropanol, water, sorbitol, mannitol, xylitol, glucose, epsilon aminocaproic acid, glycine, glutamate, sodium hyaluronate, glycerin stearate, polyethylene glycol , Carboxyvinyl polymer, polyvinylpyrrolidone, polyvinyl alcohol, cetyl alcohol, isostearyl alcohol, stearyl alcohol, hexyl decanol, octyldodecanol and other alcohols, silicone oils such as methylpolysiloxane, methylphenylpolysiloxane, dodecamethylpolysiloxane , Avocado oil, almond oil, olive oil, cacao butter, beef tallow, sesame oil, small Germ oil, safflower oil, turtle oil, persimmon oil, persic oil, castor oil, grape oil, macadamia nut oil, mink oil, yellow egg oil, safflower oil, molasses, coconut oil, rosehip oil and other oils, orange luffy oil, Liquid waxes such as jojoba oil, liquid hydrocarbons such as liquid paraffin, liquid petrolatum, squalane, squalene, higher fatty acids such as lauric acid, myristic acid, oleic acid, ethyl linoleate, isopropyl myristate, hexyl laurate, myristin Examples thereof include fatty acid esters such as octyl dodecyl acid, decyl oleate, octyl dodecyl oleate, and hexyl decyl dimethyloctanoate.
安定剤としては、エデト酸ナトリウム、亜硫酸ナトリウム、亜硫酸水素ナトリウム、チオ硫酸ナトリウム、ジブチルヒドロキシトルエン、トコフェロールなどを挙げることができる。
清涼化剤としては、メントール、ハッカ油、カンフル、ユーカリ油などを挙げることができる。
Examples of the stabilizer include sodium edetate, sodium sulfite, sodium hydrogen sulfite, sodium thiosulfate, dibutylhydroxytoluene, tocopherol and the like.
Examples of the refreshing agent include menthol, mint oil, camphor, and eucalyptus oil.
保存剤としては、パラオキシ安息香酸エステル類、クロロブタノール、フェニルエチルアルコール、塩化ベンザルコニウム、塩化ベンゼトニウム、グルコン酸クロルヘキシジン、アルキルポリアミノエチルグリシン類、ソルビン酸などが挙げることができる。
pH調整剤としては、塩酸、硫酸、酢酸、乳酸、クエン酸、酒石酸、リンゴ酸、リン酸、ホウ酸、水酸化ナトリウム、水酸化カリウム、水酸化カルシウム、モノエタノールアミン、ジエタノールアミン、ジエチルアミン、アンモニア及びこれらの塩類などを挙げることができる。
Examples of the preservative include p-hydroxybenzoates, chlorobutanol, phenylethyl alcohol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, alkylpolyaminoethylglycines, sorbic acid, and the like.
Examples of pH adjusters include hydrochloric acid, sulfuric acid, acetic acid, lactic acid, citric acid, tartaric acid, malic acid, phosphoric acid, boric acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, monoethanolamine, diethanolamine, diethylamine, ammonia and These salts can be mentioned.
軟膏基剤として、ワセリン、パラフィン、プラスチベース、シリコーン、豚脂、ろう類、単軟膏、単鉛硬膏、親水軟膏、親水ワセリン、精製ラノリン、アクアホール、オイセリン、ネオセリン、吸水軟膏、加水ラノリン、親水プラスチベース、マクロゴール類、ソルベース、ゲル炭化水素、などを挙げることができる。 Ointment base: Vaseline, paraffin, plastic base, silicone, lard, wax, single ointment, single lead plaster, hydrophilic ointment, hydrophilic petrolatum, purified lanolin, aquahole, euselin, neoserin, water-absorbing ointment, hydrous lanolin, hydrophilic plastin base , Macrogols, sol base, gel hydrocarbon, and the like.
次に、本発明製剤の製造方法の代表例を以下に述べるが、本発明の技術的範囲は、これらの例によって限定されるものではない。
トラニラストは、粒子径分布の中心が80μm〜100μmのものを購入できる。これを各種の粉砕・分散機にかけることにより、所定の粒子径を備えたトラニラストとすることができる。粉砕機としては、例えばボールミル、振動ボールミル、遠心ボールミル、ロッドミル、ミクロンミル、ジェットミル、遠心流動ボールミル、ハンマーミル、ピンミル、アドマイザー、各種のホモジナイザー、ミキサー、超音波、高圧ホモジナイザー、超薄膜式高速回転粉砕機を例示でき、これらのうち1つあるいは2つ以上の粉砕、分散機を用いて、トラニラストを微細化することができる。これらのうち、特に超薄膜式高速回転粉砕機を好適に使用することができる。
Next, representative examples of the method for producing the preparation of the present invention will be described below, but the technical scope of the present invention is not limited by these examples.
Tranilast can be purchased with a particle size distribution center of 80 μm to 100 μm. By applying this to various pulverizers / dispersers, tranilast having a predetermined particle size can be obtained. Examples of pulverizers include ball mills, vibrating ball mills, centrifugal ball mills, rod mills, micron mills, jet mills, centrifugal fluidized ball mills, hammer mills, pin mills, atomizers, various homogenizers, mixers, ultrasonic waves, high-pressure homogenizers, and ultra-thin film type high-speed rotation. A pulverizer can be exemplified, and tranilast can be refined by using one or two or more of these pulverizers and dispersers. Among these, an ultra-thin film type high-speed rotary pulverizer can be preferably used.
本実施品の製造方法として、トラニラストに必要な場合には、pH調整剤によりpHを調整した水を加えた後、超薄膜式高速回転粉砕機を用いて粉砕分散することで、所望の粒度分布を持った微細化物とすることができる。
必要に応じ、界面活性剤及び/或いは水溶性高分子を加え、トラニラスト粒子のゼータ電位の絶対値を20mV〜150mVの範囲とした懸濁性医薬組成物を得る。
As a manufacturing method of this product, when necessary for tranilast, after adding water whose pH is adjusted with a pH adjuster, it is pulverized and dispersed using an ultra-thin film type high-speed rotary pulverizer to obtain a desired particle size distribution. A refined product having
A surfactant and / or a water-soluble polymer is added as necessary to obtain a suspendable pharmaceutical composition in which the absolute value of the zeta potential of the tranilast particles is in the range of 20 mV to 150 mV.
次に、実施例を挙げて本発明を具体的に説明する。
<1.トラニラスト微細化物の皮膚透過性試験>
縦形フランツセル(有効面積0.035cm2、リザーバー容量15mL)に、ヒト人工培養皮膚(テストスキンLSE-high、東洋紡製)を真皮層がリザーバー側になるよう固定した。リザーバー液は、20%ポリエチレングリコール溶液とした。
トラニラストは、粒子径の中心が約50μm、90%メジアン径が80μmの原末の市販品を購入して使用した。トラニラストは、原末そのもの、またはクエン酸と適量の精製水に分散した後、超薄膜式高速回転粉砕機(SS−5−100型、エム・テクニック株式会社製)にて微細化処理し粉砕した微細化物を用いた。
Next, the present invention will be specifically described with reference to examples.
<1. Skin Permeability Test of Tranilast Refinement>
Human artificial cultured skin (test skin LSE-high, manufactured by Toyobo Co., Ltd.) was fixed to a vertical Franz cell (effective area 0.035 cm 2 ,
As the tranilast, a commercially available bulk powder having a particle diameter center of about 50 μm and a 90% median diameter of 80 μm was purchased and used. Tranilast was dispersed in the bulk powder itself or citric acid and an appropriate amount of purified water, and then finely pulverized and pulverized with an ultra-thin film type high-speed rotary crusher (SS-5-100, manufactured by M Technique Co., Ltd.). A refined product was used.
ドナー側には、原末(1%)(比較例1)、原末(10%)(比較例10)、又は微細化物(1%)(比較例2)の各溶液1.0mLを加えた。ドナー側に溶液を加えた時刻をゼロ時間目とし、経時的に8時間目までリザーバー液をサンプリングした。サンプリング液中のトラニラスト濃度をHPLCにて測定し、角質側から真皮側に皮膚を移行してきたトラニラストを評価した。
結果を図1及び図2に示した。データは、3回の平均値±SDで示した。図より明らかなように、トラニラスト原末を微細化することにより、皮膚に対する透過性が、原末に比べて約3倍程度に増加することが分かった。また、トラニラストの現実的な製剤濃度限界である10%の原末を用いた場合であっても、1%の原末との間に大きな透過性の差異は認められず、微細化物の透過性には大きく及ばなかった。
On the donor side, 1.0 mL of each solution of bulk powder (1%) (Comparative Example 1), bulk powder (10%) (Comparative Example 10), or refined product (1%) (Comparative Example 2) was added. . The time at which the solution was added to the donor side was set as the zero hour, and the reservoir solution was sampled over time until the eighth hour. The concentration of tranilast in the sampling solution was measured by HPLC, and tranilast that migrated from the stratum corneum to the dermis was evaluated.
The results are shown in FIG. 1 and FIG. Data are shown as the mean of three times ± SD. As is clear from the figure, it was found that the permeability to the skin increased by about 3 times compared to the bulk powder by making the tranilast bulk powder finer. In addition, even when 10% bulk powder, which is the practical concentration limit of tranilast, is used, there is no significant difference in permeability from 1% bulk powder. It did not reach greatly.
<2.トラニラスト含有クリームの皮膚透過性試験>
トラニラストの分子内には、カルボキシル基が存在しており、カチオン存在下ではイオン型として溶解する。このため、有機アミンを用いてトラニラストを溶解させたクリームを調製し、その製剤の皮膚透過性を確認した。
モノエタノールアミンにトラニラスト原末を溶解させ、クリームに含有させて、トラニラスト含有クリーム(トラニラスト濃度1%)を調製した(比較例9)。また、トラニラスト粒子のpH変化による溶解性を評価したところ、pHが、3,4.55,6,及び7では、トラニラストが溶解せず粒子として存在した。一方、pHが、7.2及び7.5では、トラニラストが溶解し、粒子としては存在しなかった。
また、トラニラストはポリエチレングリコール(PEG)に対して高い溶解性を示すことから、PEG(商品名:マクロゴール)を用いて、上記と同じ濃度のトラニラスト含有マクロゴール軟膏を調製した(比較例6)。
<2. Skin Permeation Test of Tranilast-Containing Cream>
In the tranilast molecule, a carboxyl group is present and dissolves in an ionic form in the presence of a cation. Therefore, a cream in which tranilast was dissolved using an organic amine was prepared, and the skin permeability of the preparation was confirmed.
Tranilast powder was dissolved in monoethanolamine and contained in a cream to prepare a tranilast-containing cream (
Moreover, since tranilast shows high solubility with respect to polyethylene glycol (PEG), tranilast-containing macrogol ointment having the same concentration as above was prepared using PEG (trade name: Macrogol) (Comparative Example 6). .
これら2種類のクリームを用い、上記1と同様の操作を行い、トラニラストの皮膚透過性を確認した。
結果を図3〜図5に示した。モノエタノールアミンを用いたクリーム製剤(比較例9)においては、トラニラスト原末をそのまま用いたよりも高い皮膚透過性が認められたものの、その透過性はトラニラスト微細化物には及ばなかった。なお、マクロゴール軟膏(比較例6)については、基剤に対するトラニラストの親和性が高すぎて、皮膚に対するトラニラストの透過性は、ほとんど認められなかった。
また、pHを弱アルカリ性に調整したトラニラストを溶解させたクリームは、トラニラスト原末を用いたよりも透過性は低く、よりアルカリ性になると透過性は更に低下した(図5。なお、比較例7及び比較例8の組成については、表1〜表4を参照。)。
Using these two types of cream, the same operation as in the above 1 was performed, and the skin permeability of tranilast was confirmed.
The results are shown in FIGS. In the cream formulation using monoethanolamine (Comparative Example 9), although higher skin permeability was observed than when the tranilast bulk powder was used as it was, the permeability did not reach that of the refined tranilast. In addition, as for macrogol ointment (Comparative Example 6), the affinity of tranilast for the base was too high, and the permeability of tranilast to the skin was hardly recognized.
Moreover, the cream which melt | dissolved the tranilast which adjusted pH to weak alkalinity has lower permeability than using the tranilast bulk powder, and when it became more alkaline, the permeability further decreased (FIG. 5. Comparative Example 7 and comparison) (See Tables 1 to 4 for the composition of Example 8.)
<3.各種の微細化トラニラスト製剤による比較評価>
トラニラストは、粒子径の中心が約50μm、90%メジアン径が80μmの原末の市販品を購入して使用した。トラニラストは、原末そのもの、またはクエン酸と適量の精製水に分散した後、超薄膜式高速回転粉砕機(SS−5−100型、エム・テクニック株式会社製)にて微細化処理し粉砕した微細化物を用いた。分散液に表1〜表4に記載の成分を加え、穏やかに加温し、攪拌して軟膏基材を得た。
<3. Comparative evaluation with various miniaturized tranilast preparations>
As the tranilast, a commercially available bulk powder having a particle diameter center of about 50 μm and a 90% median diameter of 80 μm was purchased and used. Tranilast was dispersed in the bulk powder itself or citric acid and an appropriate amount of purified water, and then finely pulverized and pulverized with an ultra-thin film type high-speed rotary crusher (SS-5-100, manufactured by M Technique Co., Ltd.). A refined product was used. The ingredients listed in Tables 1 to 4 were added to the dispersion, heated gently and stirred to obtain an ointment base.
実施例1〜実施例7および比較例1〜比較例8に従って得られた各試験液につき、中心粒子径(粒子径分布の中心)および90%メジアン径を測定した。中心粒子径、及び90%メジアン径は、粒度分布測定装置(SALD−7000、島津製作所製)のフローセルを使用して求めた。また、循環液として、pH3の水溶液を用いた。各表には、それぞれのパラメータの測定結果を示した。中心粒子径(D50)、及び90%メジアン径(D90)の単位は、「μm」である。
なお、比較例6〜比較例9は、基材にトラニラストが溶解したため、粒子径が測定出来なかった。
For each test solution obtained according to Examples 1 to 7 and Comparative Examples 1 to 8, the center particle size (center of particle size distribution) and 90% median size were measured. The central particle diameter and 90% median diameter were determined using a flow cell of a particle size distribution measuring device (SALD-7000, manufactured by Shimadzu Corporation). Moreover, pH3 aqueous solution was used as a circulating liquid. Each table shows the measurement results of each parameter. The unit of the central particle diameter (D 50 ) and the 90% median diameter (D 90 ) is “μm”.
In Comparative Examples 6 to 9, since the tranilast was dissolved in the base material, the particle diameter could not be measured.
<4.メントール含有トラニラスト製剤の皮膚透過性試験(1)>
次に、上記実施例4、実施例7、及び比較例2の3種類のクリームを用い、上記1と同様の操作を行い、トラニラストの皮膚透過性を確認した。
結果を図6及び図7に示した。比較例2の薬物皮膚透過性は、3種類のクリームのうち最も低かった。また、実施例4の薬物皮膚透過性は、比較例2に比べると、約2.5倍程度であったが、十分なものとは言えなかった。一方、実施例7の皮膚透過性は、実施例4に比べると、約2.5倍程度に上昇したことから、微細化した効果とl−メントールの効果とが相乗的に作用したものと考えられた。
<4. Skin permeability test of menthol-containing tranilast preparation (1)>
Next, using the three types of creams of Example 4, Example 7, and Comparative Example 2, the same operation as 1 was performed, and the skin permeability of tranilast was confirmed.
The results are shown in FIGS. The drug skin permeability of Comparative Example 2 was the lowest among the three creams. The drug skin permeability of Example 4 was about 2.5 times that of Comparative Example 2, but it was not sufficient. On the other hand, since the skin permeability of Example 7 was increased by about 2.5 times compared to Example 4, it was considered that the effect of refinement and the effect of l-menthol acted synergistically. It was.
<5.メントール含有トラニラスト製剤の皮膚透過性試験(2)>
次に、メントールの濃度を変化させて、トラニラストの皮膚透過性に与える影響を確認した。実施例1〜実施例7、比較例1、及び比較例2の9種類のクリームを用い、上記1と同様の操作を行い、トラニラストの皮膚透過性を確認した。
<5. Skin permeability test of menthol-containing tranilast preparation (2)>
Next, the concentration of menthol was changed to confirm the effect of tranilast on skin permeability. Using nine types of creams of Examples 1 to 7, Comparative Example 1 and Comparative Example 2, the same operation as in the above 1 was performed, and the skin permeability of tranilast was confirmed.
結果を図8〜図10に示した。トラニラスト原末クリームを用いた場合(実施例1〜実施例4、比較例1)のトラニラストの皮膚透過量は、l−メントールが2%までは、その濃度に依存して増加した。しかし、4%l−メントールと2%l−メントールとの間では、トラニラストの透過量には、ほとんど変化が認められなかったことから、皮膚透過促進効果について上限があることが分かった。メントール濃度が2%のとき、トラニラスト透過量は6時間後で15μg以上となり、比較例1の約8倍の透過性を示した。
また、トラニラスト微細化物クリームを用いた場合(実施例5〜実施例7、比較例2)には、トラニラストの皮膚透過量は、l−メントールの濃度に依存して増加し、メントール濃度が2%〜4%間においても増加が認められた。全透過量は、原末を用いた場合に比べて、約2倍程度に上昇した。また、4%l−メントールと2%l−メントールとの間では、トラニラストの透過量の増加が認められた。
The results are shown in FIGS. When tranilast bulk powder was used (Examples 1 to 4 and Comparative Example 1), the amount of tranilast permeated increased depending on the concentration of l-menthol up to 2%. However, since there was almost no change in the amount of tranilast permeated between 4% l-menthol and 2% l-menthol, it was found that there was an upper limit on the skin permeation promoting effect. When the menthol concentration was 2%, the amount of tranilast permeated was 15 μg or more after 6 hours, and the permeability was about 8 times that of Comparative Example 1.
When tranilast refined cream was used (Examples 5 to 7 and Comparative Example 2), the amount of tranilast permeated through the skin increased depending on the concentration of l-menthol, and the menthol concentration was 2%. An increase was also observed between -4%. The total permeation amount increased about twice as compared with the case where the bulk powder was used. An increase in the amount of tranilast permeation was observed between 4% l-menthol and 2% l-menthol.
<6.メントール含有トラニラスト製剤の皮膚透過性試験(3)>
次に、メントール含有トラニラスト微細化物クリームのpHを変化させて、トラニラストの皮膚透過性に与える影響を確認した。実施例8、実施例9、及び比較例13の3種類のクリームを用い上記1と同様の操作を行い、トラニラストの皮膚透過性を確認した。結果を図11に示した。トラニラスト粒子が溶解しないpH4〜6.5の範囲では、pHによらず同等の効果が得られた。しかし、トラニラストが溶解するpHではトラニラストの透過は大きく低下した。
<6. Skin permeability test of menthol-containing tranilast preparation (3)>
Next, the pH of the menthol-containing tranilast refined cream was changed to confirm the effect of tranilast on the skin permeability. Using the three types of creams of Example 8, Example 9, and Comparative Example 13, the same operation as in the above 1 was performed, and the skin permeability of tranilast was confirmed. The results are shown in FIG. In the range of
<7.他の透過促進剤によるトラニラスト製剤の皮膚透過性に与える影響確認試験>
次に、l−メントール以外の透過促進剤が、トラニラストの皮膚透過性に与える影響を確認した。トラニラスト原末クリームの皮膚透過促進効果を示したミリスチン酸イソプロピル(IPM)(比較例4)とベンジルアルコール(比較例5)の2種類について、トラニラストの皮膚透過促進効果を確認した。
比較例1〜比較例5、比較例11、比較例12、及び実施例7について、上記1と同様の操作を行い、トラニラストの皮膚透過性を確認した。なお、IPMおよびベンジルアルコールについては、比較例4及び比較例5のトラニラスト原末に代えて、微細化物を用いて、同様のクリームを処方したものの皮膚透過性を確認した。
<7. Test to confirm the effect of other permeation enhancers on the skin permeability of tranilast preparations>
Next, the effect of permeation enhancers other than 1-menthol on the skin permeability of tranilast was confirmed. The skin permeation promoting effect of tranilast was confirmed for two types of isopropyl myristate (IPM) (Comparative Example 4) and benzyl alcohol (Comparative Example 5), which showed the skin permeation promoting effect of Tranilast bulk powder.
About Comparative Example 1- Comparative Example 5, Comparative Example 11, Comparative Example 12, and Example 7, operation similar to said 1 was performed and the skin permeability of tranilast was confirmed. In addition, about IPM and benzyl alcohol, it replaced with the tranilast bulk powder of the comparative example 4 and the comparative example 5, and confirmed the skin permeability | transmittance of what prescribed the same cream using the refinement | miniaturization thing.
結果を図12〜図14に示した。2%IPPを添加したクリームについては、トラニラスト原末(比較例1)に比べると、皮膚透過性の向上は認められず、2%ベンジルアルコール及び2%IPMを添加したクリームについては、僅かな皮膚透過性の向上が認められたものの、その効果はトラニラスト微細化物(比較例2)と同程度であり、IPMを用いた場合であっても6時間後でも最大値(比較例4)は5μg/mLを越えなかった(図12)。また、トラニラスト微細化物を用いた場合であっても、4%l−メントールの効果には、全く及ばなかった(図13、図14)。
この結果より、微細化トラニラスト含有クリームについて、皮膚透過性を向上させるために添加する透過促進剤には、高度な選択性があることが分かった。特に、有効な透過促進剤としては、l−メントールが選択されることが分かった。
The results are shown in FIGS. As for the cream to which 2% IPP was added, the skin permeability was not improved as compared with the tranilast bulk powder (Comparative Example 1), and the cream to which 2% benzyl alcohol and 2% IPM were added showed little skin. Although an improvement in permeability was observed, the effect was similar to that of the refined tranilast (Comparative Example 2), and the maximum value (Comparative Example 4) was 5 μg / day even after 6 hours even when using IPM. It did not exceed mL (Figure 12). Moreover, even when the refined tranilast was used, the effect of 4% l-menthol was not reached at all (FIGS. 13 and 14).
From this result, it was found that the permeation enhancer added to improve the skin permeability of the refined tranilast-containing cream has a high degree of selectivity. In particular, it has been found that l-menthol is selected as an effective permeation enhancer.
<8.ラットを用いた皮膚透過性試験>
ラットをエーテルを用いて麻酔した後、腹部を剃毛し、ガラス製の内径20mmのリングを固定し、リングの内面に空気を巻き込まないよう、実施例5、実施例6、実施例7及び比較例1、比較例2、比較例9の膏体2gを塗り、5時間放置したのち、リング並びに膏体を取り外し、皮膚を摘出した。摘出した皮膚は精製水でよく洗ったのち、重量を正確に計り、精製水を加えホモジナイズした。この液に酢酸エチルを加え激しく攪拌した後、酢酸エチルを正確に計り取り、蒸発乾固したのち薬物濃度をHPLCを用いて測定した。
結果を図15に示した。比較例1、2、9と比較し、実施例5、6、7では約8〜13倍皮膚組織中の薬物濃度が高くなった。
<8. Skin permeability test using rats>
Rats were anesthetized with ether, then the abdomen was shaved, a glass ring with an inner diameter of 20 mm was fixed, and air was not caught on the inner surface of the ring. Example 5, Example 6, Example 7 and comparison After applying 2 g of the plaster of Example 1, Comparative Example 2 and Comparative Example 9, and leaving it to stand for 5 hours, the ring and the plaster were removed, and the skin was removed. The extracted skin was thoroughly washed with purified water, weighed accurately, and purified water was added and homogenized. Ethyl acetate was added to this solution and stirred vigorously, and then the ethyl acetate was accurately measured and evaporated to dryness, and then the drug concentration was measured using HPLC.
The results are shown in FIG. Compared with Comparative Examples 1, 2, and 9, in Examples 5, 6, and 7, the drug concentration in the skin tissue was about 8 to 13 times higher.
このように本実施形態によれば、安全性が高く、皮膚からの有効成分の吸収性に極めて優れ、安定性が良好であり、且つ刺激性の少ないトラニラスト含有医薬組成物を提供することができる。 As described above, according to the present embodiment, it is possible to provide a tranilast-containing pharmaceutical composition that has high safety, is extremely excellent in absorbability of active ingredients from the skin, has good stability, and has little irritation. .
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