WO2012133492A1 - 製剤安定性に優れた軟膏剤 - Google Patents
製剤安定性に優れた軟膏剤 Download PDFInfo
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- WO2012133492A1 WO2012133492A1 PCT/JP2012/058072 JP2012058072W WO2012133492A1 WO 2012133492 A1 WO2012133492 A1 WO 2012133492A1 JP 2012058072 W JP2012058072 W JP 2012058072W WO 2012133492 A1 WO2012133492 A1 WO 2012133492A1
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- ointment
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- 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
Definitions
- the present invention is capable of stably maintaining an ointment excellent in formulation stability, in particular, a naphthalene derivative useful as a PDE4 inhibitor, having excellent drug uniformity in the formulation, and suitable hardness and physical properties that are easy to apply.
- the present invention relates to an ointment having mechanical stability.
- naphthalene derivatives having a specific chemical structure have been reported as active ingredients having PDE4 inhibitory action, and pharmaceutical compositions for preventing and treating asthma using the action effects, dermatitis therapeutic agents and skin Injury treatment agents are also known (for example, Patent Documents 1 to 4 below).
- an active ingredient is a drug for which it is difficult to ensure the stability of the preparation.
- it is easily considered to increase the hardness of the preparation, but in that case, there is a problem that it becomes difficult to apply. there were.
- the present invention eliminates the above-mentioned problems in the prior art, can stably maintain a drug having a PDE4 inhibitory action, is excellent in drug uniformity in the preparation, and is suitable for easy application. It is an object to provide an ointment having hardness and physical stability (bleeding, etc.). As a result of various studies, the present inventors have selected and formulated appropriate pH regulators, antioxidants, bases, and separation inhibitors to stabilize a drug having PDE4 inhibitory activity and The present invention was completed by finding that uniformization can be achieved, bleeding can be suppressed, and a formulation hardness suitable for application can be obtained.
- excellent drug stability by blending a separation inhibitor selected from the group consisting of glycol and polyoxyethylene (54) polyoxypropylene (39) glycol, and blending a gelled hydrocarbon as a base And drug uniformity has been achieved and this ointment 1-5% by weight of 1- [2-[(4S) -4-hydroxy-1,2,3,4-tetrahydroquinolin-1-yl] -4-pyridyl] -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene 3/2 hydrate, 3-7% by weight of polyoxyethylene (196) polyoxypropylene (67) glycol, cetostearyl alcohol, behenyl alcohol, cetyl palmitate, polyoxyethylene (160) polyoxypropylene (30
- the present invention provides the ointment having the above characteristics, wherein the separation inhibitor is polyoxyethylene (196) polyoxypropylene (67) glycol, the pH adjuster is diisopropanolamine, It is also characterized in that the oxidizing agent is dibutylhydroxytoluene.
- the ointment having the above characteristics further contains at least 3% by weight of 1,3-butylene glycol.
- a drug (ointment) containing a PDE4 inhibitory drug which has been difficult to ensure the formulation stability so far, is provided, and the quality required for the drug can be ensured.
- the active ingredient in the present invention is 1- [2-[(4S) -4-hydroxy-1,2,3,4-tetrahydroquinoline-] which is one of naphthalene derivatives known to have a PDE4 inhibitory action.
- 1-yl] -4-pyridyl] -2,3-bis (hydroxymethyl) -6,7-dimethoxynaphthalene ⁇ 3/2 hydrate, and this compound (molecular formula: C 28 H 28 N 2 O 5 ⁇ 3 / 2H 2 O) has the following structural formula:
- the amount of the above-mentioned drug in the ointment of the present invention is 1 to 5% by weight, more preferably 1.25 to 5% by weight.
- concentration is less than 1% by weight, the stability and dispersibility of the drug
- concentration exceeds 5% by weight, drug precipitation occurs, which is not preferable.
- the blending amount of glycol or polyoxyethylene (54) polyoxypropylene (39) glycol is 3 to 7% by weight. When the blending amount is less than 3% by weight, it becomes difficult to ensure drug uniformity, On the other hand, if it exceeds 7% by weight, the hardness of the preparation becomes so high that it becomes difficult to apply, and the adhesion is also lowered, which is not preferable.
- polyoxyethylene (196) polyoxypropylene (67) glycol a commercially available product, for example, Unilube 70DP-950B (trade name) manufactured by NOF Corporation can be used.
- This polyoxyethylene (196) polyoxypropylene (67) glycol is a compound also referred to as polyoxyethylene (200) polyoxypropylene glycol (70).
- polyoxyethylene (160) polyoxypropylene (30) glycol commercially available products such as Adeka Pluronic F-68 (trade name) manufactured by ADEKA Corporation, polyoxyethylene (54) polyoxypropylene (39) glycol
- Adeka Pluronic P-85 trade name
- the gelled hydrocarbon in the present invention is used as an external ointment base, and for example, Plastibase (registered trademark) can be used.
- the blending amount of the gelled hydrocarbon is 15 to 50% by weight. When the blending amount is less than 15% by weight, it is difficult to ensure the preparation quality in terms of drug uniformity and bleeding. Exceeding% by weight is not preferable because the hardness of the preparation increases and it becomes difficult to apply.
- the blending amount of diisopropanolamine (DIPA), citric acid hydrate, lactic acid, triisopropanolamine, triethanolamine, and monoethanolamine blended as a pH adjuster in the ointment of the present invention is the main phase of the ointment. Any amount that can adjust the pH in the range of 8 to 10.5 may be used.
- the main drug phase refers to a uniform one-phase solution in which a drug, a pH regulator and an antioxidant are dissolved in an aqueous base (for example, 1,3-butylene glycol). The pH of the main drug phase is measured.
- DIPA is used as a pH adjuster, the blending amount is 0.04 to 5% by weight.
- the blending amount is less than 0.04% by weight, the stability of the drug is poor and the degradation product immediately after preparation Concentration exceeding 5% by weight (the upper limit of the amount of pharmaceutical preparations used in general external preparations) exceeds the concentration of general external preparations used in pharmaceuticals, and safety has not been confirmed so far. It is not preferable.
- BHT Dibutylhydroxytoluene
- BHA butylhydroxyanisole
- BHA butylhydroxyanisole
- tocopherol pentaerythryl-tetrakis [3- (3, blended as antioxidant (stabilizer) in the ointment of the present invention
- the amount of 5-di-tert-butyl-4-hydroxyphenyl) propionate] is 0.05 to 0.4% by weight, and if it is less than 0.05% by weight, the stability of the drug is poor and a decomposition product is formed.
- BHT antioxidant
- it is not appropriate to add BHT unnecessarily as a pharmaceutical product, and the optimum range is the above range.
- 1,3-butylene glycol as a solubilizer may be blended in at least 3% by weight, preferably 3 to 20% by weight.
- the ointment of the present invention may be mixed with beeswax wax or stearyl alcohol as a base other than the gelled hydrocarbon, and petrolatum (preferably white petrolatum) in a total amount of 100% by weight. May be blended.
- the ointment preparation of the present invention can be produced according to a general ointment production method.
- base component gelled hydrocarbon, white petrolatum, white beeswax, stearyl alcohol
- separation inhibitor polyoxyethylene (196) polyoxypropylene (67) glycol, etc.
- An oil phase is prepared by mixing uniformly, and then (2) a drug, a solubilizer (1,3-butylene glycol, etc.), a pH adjuster (diisopropanolamine, citric acid hydrate, etc.) )
- an antioxidant such as dibutylhydroxytoluene
- the ointment preparation of Comparative Example 6 or 7 uses microcrystalline wax or ceresin instead of gelled hydrocarbon, and the ointment preparation of Comparative Example 12, 13, 14, 15 or 16 uses polyoxyethylene (196) poly It was produced using polyoxyethylene glycol monostearate, sorbitan monostearate, glyceryl monostearate, stearic acid or sucrose fatty acid ester instead of oxypropylene (67) glycol.
- Comparative Test on Drug Stability Ointments (Examples 1 to 6 and Comparative Examples 1 and 2) having the compositions shown in Table 1 below were prepared. At the time of preparation (Initial), 40 ° C./75% RH The stability of the drug was evaluated by measuring the amount of degradation products after storage for 1 month and after storage at 40 ° C./75% RH for 3 months and after storage at 60 ° C. for 4 weeks. As stability criteria (quality assurance index), degradation products after storage at 40 ° C / 75% RH for 3 months do not exceed 0.1%, or degradation after storage at 60 ° C for 2 weeks The case where the product did not exceed 0.1% or the case where the degradation product after storage at 60 ° C. for 4 weeks did not exceed 0.2% was judged as “good drug stability”.
- the content relative standard deviation indicates the relative standard deviation of the contents obtained by collecting samples from the upper, middle and lower parts of the storage container.
- the hardness of the preparation is determined to be 6.0 mm or more, based on the quality standard that the penetration is measured at 25 ° C. using a penetrometer and is not inferior to that of a commercially available general external preparation. It was judged. In addition, about bleeding, the case of 5% or less was judged as "good".
- the blending amount of polyoxyethylene (196) polyoxypropylene (67) glycol is 8% by weight or more (Comparative Examples 9 to 11)
- the hardness and adhesion of the preparations deviated from the judgment criteria, and the usability was There was a tendency to get worse.
- the ointment of the present invention is a preparation that can obtain excellent values in drug uniformity, hardness, bleeding and adhesion, and can ensure the quality as an external preparation. It was confirmed. From these results, the optimum blending amount of polyoxyethylene (196) polyoxypropylene (67) glycol was determined to be 3 to 7% by weight.
- Adhesion comparison with commercially available ointment The adhesion comparison between a commercially available general external preparation and the ointment of the present invention having the composition of Example 2 was performed. The measurement results are shown in Table 7 below. The measurement method is the same as described above.
- the ointment of the present invention having the composition of Example 2 is also problematic in terms of adhesiveness, which is an index for evaluating the stickiness of the preparation, in the same manner as commercially available general external preparations. It was confirmed that it was not.
- the ointment of the present invention is excellent in the stability and uniformity of the drug in the preparation, has hardness and physical stability suitable for application, and according to the present invention, it is possible to ensure the quality required for pharmaceutical products. .
Abstract
Description
しかしながら、このような有効成分は、製剤の安定性を確保することが困難な薬剤であった。又、軟膏剤中の薬物の均一性やブリーディングを確保するための解決方法として、製剤の硬度を硬くすることが容易に考えられるが、その場合には、塗布することが難しくなるという問題点があった。
本発明者等は、種々検討を行った結果、適切なpH調節剤、抗酸化剤、基剤及び分離抑制剤を選択して配合することによって、PDE4阻害作用を有する薬物の安定化及び薬物の均一化を達成でき、且つ、ブリーディングを抑制でき、塗布に適した製剤硬度が得られることを見出して、本発明を完成した。
1~5重量%の1-[2-[(4S)-4-ヒドロキシ-1,2,3,4-テトラヒドロキノリン-1-イル]-4-ピリジル]-2,3-ビス(ヒドロキシメチル)-6,7-ジメトキシナフタレン・3/2水和物、
3~7重量%の、ポリオキシエチレン(196)ポリオキシプロピレン(67)グリコール、セトステアリルアルコール、ベヘニルアルコール、パルミチン酸セチル、ポリオキシエチレン(160)ポリオキシプロピレン(30)グリコールおよびポリオキシエチレン(54)ポリオキシプロピレン(39)グリコールから成る群より選ばれる1種以上の分離抑制剤、
15~50重量%の、ゲル化炭化水素、
ジイソプロパノールアミン、クエン酸水和物、乳酸、トリイソプロパノールアミン、トリエタノールアミンおよびモノエタノールアミンから成る群より選ばれるpH調節剤、及び、
0.05~0.4重量%の、ジブチルヒドロキシトルエン、ブチルヒドロキシアニソール、没食子酸プロピル、トコフェロールおよびペンタエリスチル‐テトラキス[3‐(3,5‐ジ‐t‐ブチル‐4‐ヒドロキシフェニル)プロピオネート]から成る群より選ばれる抗酸化剤
を含有することを特徴とする。
又、本発明は、上記の特徴を有した軟膏剤において、更に少なくとも3重量%の1,3‐ブチレングリコールを含有することを特徴とするものでもある。
本発明における有効成分は、PDE4阻害作用を有することが知られているナフタレン誘導体の1種である
1-[2-[(4S)-4-ヒドロキシ-1,2,3,4-テトラヒドロキノリン-1-イル]-4-ピリジル]-2,3-ビス(ヒドロキシメチル)-6,7-ジメトキシナフタレン・3/2水和物であり、この化合物(分子式:C28H28N2O5・3/2H2O)は、以下の構造式を有する。
以下に、本発明の軟膏剤の実施例を示す。
なお、比較例6または7の軟膏製剤は、ゲル化炭化水素に代えてマイクロクリスタリンワックスまたはセレシンを用い、比較例12、13、14、15または16の軟膏製剤は、ポリオキシエチレン(196)ポリオキシプロピレン(67)グリコールに代えてモノステアリン酸ポリオキシエチレングリコール、モノステアリン酸ソルビタン、モノステアリン酸グリセリン、ステアリン酸またはショ糖脂肪酸エステルを用いて製造した。
以下の表1に示される組成を有した軟膏剤(実施例1~6及び比較例1,2)を調製し、調製時(Initial)と、40℃/75%RH・1ヶ月保存後、及び40℃/75%RH・3ヶ月保存後、及び、60℃・4週間保存後の分解物生成量を測定することによって薬物の安定性を評価した。安定性の判断基準(品質確保の指標)としては、40℃/75%RH・3ヶ月保存後の分解生成物が0.1%を超えない場合、又は、60℃・2週間保存後の分解生成物が0.1%を超えない場合、又は、60℃・4週間保存後の分解生成物が0.2%を超えない場合を「薬物の安定性が良好」と判断した。
尚、この比較試験では、「ゲル化炭化水素」として、市販の「プラスチベース」(ブリストル・マイヤーズ社製)を使用し、「ポリオキシエチレン(196)ポリオキシプロピレン(67)グリコール(分離抑制剤)」として、市販の「ユニルーブ70DP-950B」(日油株式会社製)を使用した。クエン酸水和物の配合量は0.02重量%、サラシミツロウの配合量は5重量%、ステアリルアルコールの配合量は5重量%、白色ワセリンの配合量は、全量が100重量%となる量とした。
同様に、DIPAを含まない比較例2では、Initial(調製直後)からすでに分解物が生成しており、薬物の安定性が確保できない処方であることがわかった。一方、DIPAを0.04重量%、0.8重量%及び5重量%含有する実施例1~6の軟膏剤の場合には、薬物の安定性は良好であった。上記実施例1~6の軟膏剤の主薬相pHは、8~10.5の範囲であった。
以下の表2に示される組成を有した軟膏剤(実施例1、7、8及び比較例3~5)を調製し、ゲル化炭化水素の配合量の違いによる薬物均一性、製剤硬度、ブリーディングを比較した。上記の3つの評価項目は、それぞれが製剤の品質を評価したものである。そのうち、硬度とブリーディングについては、使用感につながる評価である。
表2における薬物均一性については、含量相対標準偏差が、調製時(Initial)では3%を超えないこと、経時的評価(40℃・1ヶ月又は2ヶ月)では6%を超えないことを、均一性良好の判断基準とした。なお、含量相対標準偏差は、保存容器の上部、中部、下部からそれぞれ試料を採取し、その含量の相対標準偏差を示したものである。又、製剤硬度は、ペネトロメーターを用いて25℃における針入度を測定し、市販されている一般外用剤のものと比較して劣らないことを品質の基準とし、6.0mm以上を良好と判断した。尚、ブリーディングについては、5%以下の場合を「良好」と判断した。
又、分離抑制剤として添加されるポリオキシエチレン(196)ポリオキシプロピレン(67)グリコールの配合量については、2重量%の配合で、製剤の硬度及び付着性は問題なく適切な値を示したが、薬物均一性を確保することはできなかった(比較例8)。また、ポリオキシエチレン(196)ポリオキシプロピレン(67)グリコールの配合量が8重量%以上の場合(比較例9~11)には、製剤の硬度及び付着性が判定基準を外れ、使用感が悪くなる傾向があった。これに対して、本発明の軟膏剤(実施例2、9、10)は、薬物均一性、硬度、ブリーディング及び付着性において優れた値が得られ、外用製剤としての品質を確保できる製剤であることが確認された。このような結果から、ポリオキシエチレン(196)ポリオキシプロピレン(67)グリコールの最適配合量は3~7重量%であると判断した。
軟膏剤に配合される分離抑制剤を、ポリオキシエチレン(196)ポリオキシプロピレン(67)グリコールから他の化合物に変更した製剤についての検討を実施した。分離抑制剤として検討した化合物は、以下の表5に記載されるモノステアリン酸エステル系の界面活性剤、高級脂肪酸化合物及びショ糖脂肪酸エステルである。
市販されている一般外用剤と、前記実施例1及び2の組成を有した本発明の軟膏剤との硬度比較を行った。測定結果を以下の表6に示す。尚、測定方法は前記と同様である。
市販されている一般外用剤と、前記実施例2の組成を有した本発明の軟膏剤との付着性比較を行った。測定結果を以下の表7に示す。測定方法は前記と同様である。
Claims (3)
- 1~5重量%の、1-[2-[(4S)-4-ヒドロキシ-1,2,3,4-テトラヒドロキノリン-1-イル]-4-ピリジル]-2,3-ビス(ヒドロキシメチル)-6,7-ジメトキシナフタレン・3/2水和物、
3~7重量%の、ポリオキシエチレン(196)ポリオキシプロピレン(67)グリコール、セトステアリルアルコール、ベヘニルアルコール、パルミチン酸セチル、ポリオキシエチレン(160)ポリオキシプロピレン(30)グリコールおよびポリオキシエチレン(54)ポリオキシプロピレン(39)グリコールから成る群より選ばれる分離抑制剤、
15~50重量%の、ゲル化炭化水素、
ジイソプロパノールアミン、クエン酸水和物、乳酸、トリイソプロパノールアミン、トリエタノールアミンおよびモノエタノールアミンから成る群より選ばれるpH調節剤、及び、
0.05~0.4重量%の、ジブチルヒドロキシトルエン、ブチルヒドロキシアニソール、没食子酸プロピル、トコフェロールおよびペンタエリスチル‐テトラキス[3‐(3,5‐ジ‐t‐ブチル‐4‐ヒドロキシフェニル)プロピオネート]から成る群より選ばれる抗酸化剤
を含有することを特徴とする軟膏剤。 - 前記分離抑制剤がポリオキシエチレン(196)ポリオキシプロピレン(67)グリコールであり、前記pH調節剤がジイソプロパノールアミンであり、前記抗酸化剤がジブチルヒドロキシトルエンであることを特徴とする請求項1に記載の軟膏剤。
- 更に、少なくとも3重量%の1,3‐ブチレングリコールを含有することを特徴とする請求項1又は2に記載の軟膏剤。
Priority Applications (4)
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ES12762791.7T ES2631603T3 (es) | 2011-03-31 | 2012-03-28 | Pomada con excelente estabilidad de formulación |
EP12762791.7A EP2692347B1 (en) | 2011-03-31 | 2012-03-28 | Ointment with excellent formulation stability |
US14/008,413 US9555025B2 (en) | 2011-03-31 | 2012-03-28 | Ointment with excellent formulation stability |
JP2013507654A JP5898676B2 (ja) | 2011-03-31 | 2012-03-28 | 製剤安定性に優れた軟膏剤 |
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JP2011-080154 | 2011-03-31 | ||
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US (1) | US9555025B2 (ja) |
EP (1) | EP2692347B1 (ja) |
JP (1) | JP5898676B2 (ja) |
ES (1) | ES2631603T3 (ja) |
TW (1) | TW201247241A (ja) |
WO (1) | WO2012133492A1 (ja) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017089347A1 (en) | 2015-11-25 | 2017-06-01 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Methods and pharmaceutical compositions for the treatment of braf inhibitor resistant melanomas |
JP2019535708A (ja) * | 2016-11-10 | 2019-12-12 | メディスカ ファーマシューティック インコーポレイテッド | 薬剤の配合方法およびシステム |
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- 2012-03-28 EP EP12762791.7A patent/EP2692347B1/en not_active Not-in-force
- 2012-03-28 US US14/008,413 patent/US9555025B2/en not_active Expired - Fee Related
- 2012-03-28 WO PCT/JP2012/058072 patent/WO2012133492A1/ja active Application Filing
- 2012-03-28 ES ES12762791.7T patent/ES2631603T3/es active Active
- 2012-03-28 JP JP2013507654A patent/JP5898676B2/ja not_active Expired - Fee Related
- 2012-03-30 TW TW101111324A patent/TW201247241A/zh unknown
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JPH0959255A (ja) | 1995-06-15 | 1997-03-04 | Tanabe Seiyaku Co Ltd | ナフタレン誘導体、その製法及びその合成中間体 |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017089347A1 (en) | 2015-11-25 | 2017-06-01 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Methods and pharmaceutical compositions for the treatment of braf inhibitor resistant melanomas |
JP2019535708A (ja) * | 2016-11-10 | 2019-12-12 | メディスカ ファーマシューティック インコーポレイテッド | 薬剤の配合方法およびシステム |
US11883359B2 (en) | 2016-11-10 | 2024-01-30 | Medisca Pharmaceutique Inc. | Adapter for use in a planetary mixer |
Also Published As
Publication number | Publication date |
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JP5898676B2 (ja) | 2016-04-06 |
EP2692347A4 (en) | 2014-09-17 |
EP2692347B1 (en) | 2017-03-08 |
EP2692347A1 (en) | 2014-02-05 |
JPWO2012133492A1 (ja) | 2014-07-28 |
US20140018387A1 (en) | 2014-01-16 |
US9555025B2 (en) | 2017-01-31 |
ES2631603T3 (es) | 2017-09-01 |
TW201247241A (en) | 2012-12-01 |
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