JP2017066074A - Atopic dermatitis therapeutic agent - Google Patents
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Abstract
Description
本発明は、副腎皮質ステロイド外用薬並みの治療効果があり、なおかつ皮膚への副作用の少ないアトピー性皮膚炎治療薬に関する。さらに詳しくは、本発明は、Ｒ−フルルビプロフェンを用いることにより、副腎皮質ステロイド外用薬並みの治療効果があり、なおかつ皮膚への副作用の少ないアトピー性皮膚炎治療薬に関するものである。 The present invention relates to a therapeutic agent for atopic dermatitis which has therapeutic effects similar to those of topical corticosteroids and has few side effects on the skin. More specifically, the present invention relates to a therapeutic agent for atopic dermatitis having the same therapeutic effect as that of a topical corticosteroid and having few side effects on the skin by using R-flurbiprofen.
近年、西欧型ライフスタイルへの変化とともにアレルギー性疾患（アレルギー性鼻炎、花粉症、気管支喘息、アトピー性皮膚炎など）の患者数が増加し、大きな問題となっている。特に、アトピー性皮膚炎は、乳幼児の１０％以上の有症率を示すほど、乳幼児に多い疾患であり、成長に伴い他のアトピー性疾患を合併しやすい事などから、患者、家族の不安が非常に大きい疾患である。 In recent years, the number of patients with allergic diseases (allergic rhinitis, hay fever, bronchial asthma, atopic dermatitis, etc.) has increased with the change to Western-style lifestyles, which has become a major problem. In particular, atopic dermatitis is a disease that is more common in infants as it shows a prevalence of more than 10% of infants, and it is easy for patients to have other atopic diseases with their growth. It is a very big disease.
このアトピー性皮膚炎の治療には、副腎皮質ステロイド外用薬、免疫抑制外用薬および経口抗アレルギー薬が主に用いられている（非特許文献１）。しかし、これらの治療薬を使用してもコントロールが不良な症例も多く、この場合は、最も治療効果の高い副腎皮質ステロイド外用薬を長期間使用し治療を行う必要がある。しかし、副腎皮質ステロイド外用薬は、長期間連続使用すると皮膚の委縮、毛細血管拡張、ニキビ、多毛などの副作用が発現する事（非特許文献２）があり、副腎皮質ステロイド外用薬の長期使用は制限されているため、十分なアトピー性皮膚炎治療が行えない課題があった。 For the treatment of atopic dermatitis, corticosteroid topical drugs, immunosuppressive drugs, and oral antiallergic drugs are mainly used (Non-patent Document 1). However, there are many cases in which control is poor even when these therapeutic agents are used, and in this case, it is necessary to treat with long-term use of a topical corticosteroid with the highest therapeutic effect. However, when a corticosteroid topical drug is used continuously for a long period of time, side effects such as skin atrophy, telangiectasia, acne, and hirsutism may occur (Non-patent Document 2). Due to the limitation, there is a problem that sufficient atopic dermatitis treatment cannot be performed.
この様な状況から、副腎皮質ステロイド外用薬並みの治療効果があり、なおかつ皮膚への副作用の少ないアトピー性皮膚炎治療薬の開発が求められている。 Under such circumstances, there is a demand for the development of a therapeutic agent for atopic dermatitis that is as effective as a topical corticosteroid and has few side effects on the skin.
本発明の目的は、上述の状況を鑑みてなされたもので、副腎皮質ステロイド外用薬並みの治療効果があり、なおかつ皮膚への副作用の少ないアトピー性皮膚炎治療薬を提供することである。 An object of the present invention is to provide a therapeutic drug for atopic dermatitis which has been made in view of the above-described circumstances and has therapeutic effects similar to those of a topical corticosteroid and has few side effects on the skin.
本発明者らは、前記課題を解決すべく鋭意研究を重ねた結果、フルルビプロフェンの光学異性体Ｒ体（Ｒ−フルルビプロフェン）のみを用いることにより、アトピー性皮膚炎に対して副腎皮質ステロイド外用薬並みの強い治療効果を発現し、なおかつ皮膚への副作用が少ないアトピー性皮膚炎治療薬を得る事ができることを見出し、この知見に基づき、本発明を完成するに至った。
すなわち、本発明は、以下の（１）〜（２）に示したものである。
（１）Ｒ−フルルビプロフェンを有効成分とすることを特徴とするアトピー性皮膚炎治療薬。
（２）外用剤として適用することを特徴とする上記（１）に記載のアトピー性皮膚炎治療薬。
As a result of intensive studies to solve the above-described problems, the present inventors have used only the optical isomer R form of flurbiprofen (R-flurbiprofen) to prevent atopic dermatitis. The present inventors have found that a therapeutic agent for atopic dermatitis that exhibits a strong therapeutic effect similar to that of a topical corticosteroid and that has few side effects on the skin can be obtained. Based on this finding, the present invention has been completed.
That is, this invention is shown to the following (1)-(2).
(1) A therapeutic agent for atopic dermatitis comprising R-flurbiprofen as an active ingredient.
(2) The therapeutic agent for atopic dermatitis according to (1), which is applied as an external preparation.
以上に述べたように、本発明は、Ｒ−フルルビプロフェンを有効成分とするアトピー性皮膚炎治療薬であって、副腎皮質ステロイド外用薬並みの治療効果があり、なおかつ皮膚への副作用が少ないアトピー性皮膚炎治療薬を提供することができる。 As described above, the present invention is a therapeutic agent for atopic dermatitis comprising R-flurbiprofen as an active ingredient, which has therapeutic effects similar to those of topical corticosteroids and has side effects on the skin. Fewer atopic dermatitis therapeutic agents can be provided.
以下、本発明のアトピー性皮膚炎治療薬を詳細に説明する。なお、本明細書に記載の例示は、本発明を特に限定するものではない。 Hereinafter, the therapeutic agent for atopic dermatitis of the present invention will be described in detail. Note that the examples described in the present specification do not particularly limit the present invention.
本発明で使用するＲ−フルルビプロフェンとは、フルルビプロフェンの光学異性体Ｒ体の事で、（２Ｒ）−２−（２−Ｆｌｕｏｒｏｂｉｐｈｅｎｙｌ−４−ｙｌ）ｐｒｏｐａｎｏｉｃ ａｃｉｄの化学名で表される化合物である。 The R-flurbiprofen used in the present invention is an optical isomer R form of flurbiprofen, represented by the chemical name of (2R) -2- (2-Fluorobiphenyl-4-yl) propanoic acid. It is a compound.
本発明の「副腎皮質ステロイド外用薬並みの治療効果」とは、アトピー性皮膚炎モデルとして汎用されているマウスダニ抗原誘発アトピー性皮膚炎モデルを用いてアトピー性皮膚炎抑制試験を行った際の耳介厚（耳浮腫の程度）の抑制効果の強さを意味し、軟膏剤を投与していない対照群の耳介厚抑制率に対する有意差検定（Ｄｕｎｎｅｔｔの検定）を行い、有意な差（ｐ＜０．０５）があり、なおかつ代表的な副腎皮質ステロイド外用薬である吉草酸ベタメタゾンの０．１２％軟膏剤（比較例５）の耳介厚抑制率のプラスマイナス５％の範囲内であった場合を、「副腎皮質ステロイド外用薬並みの治療効果あり」とした。 The “therapeutic effect equivalent to that of a topical corticosteroid” according to the present invention refers to an ear when atopic dermatitis suppression test is performed using a mouse tick antigen-induced atopic dermatitis model that is widely used as an atopic dermatitis model. This means the strength of the effect of suppressing the thickness of the ear (the degree of ear edema). A significant difference test (Dunnett's test) was performed on the suppression rate of the ear thickness of the control group to which the ointment was not administered. <0.05), and within a range of 5% of the suppression rate of auricle thickness of 0.12% ointment (Comparative Example 5) of betamethasone valerate, which is a typical topical corticosteroid topical drug. In this case, it was said to have “the same therapeutic effect as topical corticosteroids”.
本発明の「皮膚への副作用」とは、１４日間反復経皮投与毒性試験を行った際の軟膏剤適用部位（皮膚）の病理組織学的所見における「上皮の壊死」、「真皮の壊死」および「皮膚委縮」有無を意味する。「皮膚委縮」とは、病理組織標本上で上皮から真皮までの厚さ（皮膚厚）を測定し、この皮膚厚が減少する事を意味し、軟膏剤を投与していない対照群に対する有意差検定（Ｄｕｎｎｅｔｔの検定）を行い、有意な差（ｐ＜０．０５）があった場合、皮膚萎縮ありとした。「上皮の壊死」および「真皮の壊死」が「−：著変なし」または「±：ごく軽度」であり、かつ「皮膚委縮」がない場合を「皮膚への副作用がない」とした。また、「上皮の壊死」および「真皮の壊死」が「＋：軽度」、「＋＋：中等度」または「＋＋＋：強度」である、または「皮膚委縮」がある場合を「皮膚への副作用がある」とした。 The “side effects on the skin” of the present invention means “necrosis of the epithelium” and “necrosis of the dermis” in the histopathological findings of the ointment application site (skin) when the 14-day repeated dermal administration toxicity test was conducted. And “skin atrophy”. “Skin atrophy” means that the thickness from the epithelium to the dermis (skin thickness) is measured on the histopathological specimen, and this skin thickness decreases. Significant difference from the control group not administered ointment A test (Dunnett's test) was performed, and when there was a significant difference (p <0.05), skin atrophy was present. The cases where “epithelial necrosis” and “dermis necrosis” were “−: no change” or “±: very mild” and there was no “skin atrophy” were defined as “no side effects on the skin”. In addition, when “epithelial necrosis” and “dermis necrosis” are “+: mild”, “++: moderate” or “++++: strength”, or “skin atrophy”, There is.
本発明のアトピー性皮膚炎治療薬を含有する医薬品の剤形としては、本発明の効果を損なわなければ特に限定しないが、例えば、軟膏剤、ローション剤およびクリーム剤などの皮膚外用剤を挙げる事ができる。 The pharmaceutical dosage form containing the therapeutic agent for atopic dermatitis of the present invention is not particularly limited as long as the effects of the present invention are not impaired, and examples thereof include external preparations for skin such as ointments, lotions and creams. Can do.
これらの皮膚外用剤に用いる基剤としては、公知のもの、または、今後新たに提供されるものを用いればよく、特に限定はない。例えば、ワセリン、ひまし油、シリコーン、スクワラン、アクリル酸ナトリウム、ベヘニルアルコール、モノステアリン酸グリセロール、ステアリルアルコール、エタノール、バチルアルコール、フェノキシエタノール、１，３−ブチレングリコール、ミリスチン酸イソプロピル、ステアリン酸、レシチンおよび精製水などを挙げることができ、単独あるいは２種以上組み合わせて用いることができる。 As a base used for these external preparations for skin, a known one or a newly provided one may be used, and there is no particular limitation. For example, petroleum jelly, castor oil, silicone, squalane, sodium acrylate, behenyl alcohol, glycerol monostearate, stearyl alcohol, ethanol, batyl alcohol, phenoxyethanol, 1,3-butylene glycol, isopropyl myristate, stearic acid, lecithin and purified water These may be used alone or in combination of two or more.
本発明のアトピー性皮膚炎治療薬を含有する医薬品は、上記基剤成分の他に、本発明の効果を損なわない範囲で医薬品を製造するにあたって許容される各種成分、すなわち、抗酸化剤、防腐剤、湿潤剤、粘稠剤、緩衝剤、吸着剤、溶剤、乳化剤および安定化剤などの添加剤を適宜加えることができる。 In addition to the above base components, the pharmaceutical containing the therapeutic agent for atopic dermatitis of the present invention includes various components that are acceptable in the manufacture of the pharmaceutical within a range that does not impair the effects of the present invention, that is, antioxidants, antiseptics. Additives such as agents, wetting agents, thickeners, buffers, adsorbents, solvents, emulsifiers and stabilizers can be added as appropriate.
以下に実施例によりさらに詳細に本発明を説明するが、本発明はこれに限定されるものではない。
（実施例１）
後述する調製法１の方法により調製し、本発明のアトピー性皮膚炎治療薬を含有する軟膏剤１を得た。得られた軟膏剤１を用いて試験例１に従ってアトピー性皮膚炎抑制試験を行った結果、耳介厚抑制率は、３３．７±４．２％であり、対照群に対し有意な差があった。また、その耳介厚抑制率は、後述する比較例５の耳介厚抑制率３７．２±５．７％のプラスマイナス５％の範囲内であり、副腎皮質ステロイド外用薬並みの治療効果であった。さらに、試験例２に従って１４日間反復経皮投与毒性試験を行った結果、適用皮膚の病理所見において「上皮の壊死」や「真皮の壊死」は「―：著変なし」であり、また、皮膚委縮率は０．３±４．９％であり、皮膚委縮がなかったことから、皮膚への副作用がなかった。結果を表１に示す。
The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.
Example 1
The ointment 1 containing the therapeutic agent for atopic dermatitis of the present invention was obtained by the preparation method 1 described later. As a result of conducting an atopic dermatitis suppression test according to Test Example 1 using the obtained ointment 1, the auricle thickness suppression rate was 33.7 ± 4.2%, which was significantly different from the control group. there were. In addition, the pinna thickness suppression rate is within the range of plus or minus 5% of the pinna thickness suppression rate of 37.2 ± 5.7% of Comparative Example 5 described later. there were. Furthermore, as a result of a 14-day repeated dermal administration toxicity test according to Test Example 2, the pathological findings of the applied skin are “epithelial necrosis” and “dermis necrosis” as “-: no significant change”. The contraction rate was 0.3 ± 4.9%, and since there was no skin contraction, there were no side effects on the skin. The results are shown in Table 1.
（調製法１）
Ｒ−フルルビプロフェン（１．５ｇ）を乳鉢ですりつぶした後、白色ワセリン（４８．５ｇ）を少しずつ加え、十分に練合し、均一な軟膏剤を得た。
(Preparation method 1)
After grinding R-flurbiprofen (1.5 g) in a mortar, white petrolatum (48.5 g) was added little by little and kneaded thoroughly to obtain a uniform ointment.
（試験例１）
アトピー性皮膚炎抑制試験
前述の実施例１の軟膏剤および後述する比較例１乃至５の軟膏剤を使用し、次に示す方法でアトピー性皮膚炎抑制試験を行った。
６週齢のＮＣ／Ｎｇａ雄性マウスの右耳の耳介に、ダニ抗原（Ｍｉｔｅ Ｅｘｔｒａｃｔ−ＤＰ：（株）ＬＳＬ）を１日おきに６回皮内投与（５μｇ／μＬ／部位）することにより皮膚炎を惹起した。ダニ抗原投与開始から１２日目にダイヤルシックネスゲージを用いて右耳の耳介厚（耳浮腫の程度）を測定し、耳介厚を指標にマウスを７群（１群７匹）に群分けした。翌日より、無処置対照群以外の６群には右耳の両面に被験軟膏剤１５ｍｇを塗布し、この操作を１日２回１０日間連続して行った。また、被験軟膏剤投与期間にわたって、１回目の被験軟膏剤投与の直前にダイヤルシックネスゲージを用いて耳介厚を測定し、１０日間の耳介厚累積値を求めた。さらに、軟膏剤無処置対照群の耳介厚累積値に対する抑制率を算出し、耳介厚抑制率とした。
(Test Example 1)
Atopic dermatitis suppression test Using the ointment of Example 1 described above and the ointments of Comparative Examples 1 to 5 described later, an atopic dermatitis suppression test was performed by the following method.
By administering intradermally (5 μg / μL / site) of mite antigen (Mite Extract-DP: LSL) 6 times every other day to the right ear of 6-week old NC / Nga male mice Caused dermatitis. On the 12th day from the start of mite antigen administration, the right ear thickness (degree of ear edema) was measured using a dial thickness gauge, and the mice were divided into 7 groups (7 mice per group) using the ear thickness as an index. did. From the next day, 15 mg of the test ointment was applied to both sides of the right ear in 6 groups other than the untreated control group, and this operation was performed twice a day for 10 consecutive days. In addition, over the test ointment administration period, the thickness of the auricle was measured using a dial thickness gauge immediately before the first test ointment administration, and the accumulated value of the auricle thickness for 10 days was determined. Furthermore, the suppression rate with respect to the auricle thickness cumulative value of the ointment non-treated control group was calculated and used as the auricle thickness suppression rate.
（試験例２）
１４日間反復経皮投与毒性試験
前述の実施例１の軟膏剤および後述する比較例５の軟膏剤を使用し、次に示す方法で１４日間反復経皮投与毒性試験を行った。
６週齢のウイスター系雄性ラットの背部被毛を電気バリカンで毛刈りし、４ｃｍ×５ｃｍの被験区域を設けた。翌日より各被験軟膏剤３００ｍｇを被験区域に均一に塗布し、塗布部位を保護する目的で、不織布、粘着シートおよびサージカルテープで被覆した。この操作を１日１回１４日間連続して行った。正常群は、軟膏剤無処置とした。最終塗布の翌日に、軟膏剤適用部位の皮膚を摘出し、１０％中性ホルマリンで固定後、病理組織標本（ヘマトキシリン・エオジン染色）を作製した。この病理組織標本で、上皮および真皮の組織像を観察し、細胞の壊死の程度を５段階（―：著変なし、±：ごく軽度、＋：軽度、＋＋：中等度、＋＋＋：強度）で評価した。また、標本上で上皮から真皮までの厚さを測定し、皮膚厚とし、軟膏剤無処置対照群の皮膚厚に対する抑制率の平均値±標準誤差を算出し、皮膚委縮率とした。
(Test Example 2)
14-Day Repeated Dermal Dose Toxicity Test Using the ointment of Example 1 described above and the ointment of Comparative Example 5 described below, a 14-day repeated Dermal Dose Toxicity Test was performed by the following method.
The back coat of 6-week old Wistar male rats was shaved with an electric clipper to provide a test area of 4 cm × 5 cm. From the next day, 300 mg of each test ointment was uniformly applied to the test area and covered with a nonwoven fabric, an adhesive sheet and surgical tape for the purpose of protecting the application site. This operation was performed once a day for 14 consecutive days. In the normal group, the ointment was not treated. The day after the final application, the skin at the site where the ointment was applied was removed, fixed with 10% neutral formalin, and then a histopathological specimen (hematoxylin and eosin staining) was prepared. With this histopathological specimen, the histology of the epithelium and dermis is observed, and the degree of necrosis of the cells is classified into five levels (-: no change, ±: very mild, +: mild, ++: moderate, +++: intensity) evaluated. In addition, the thickness from the epithelium to the dermis was measured on the specimen to obtain the skin thickness, and the mean value ± standard error of the inhibition rate with respect to the skin thickness of the ointment untreated control group was calculated to obtain the skin atrophy rate.
（比較例１）
実施例１において、Ｒ−フルルビプロフェンを（２ＲＳ）−２−（３−Ｂｅｎｚｏｙｌｐｈｅｎｙｌ）ｐｒｏｐａｎｏｉｃ ａｃｉｄ（ケトプロフェン）にした以外は実施例１と全く同じ調製法を繰り返して、軟膏剤２を得た。得られた軟膏剤２を試験例１に従ってアトピー性皮膚炎抑制試験を行った結果、耳介厚抑制率は、−１０．８±６．４％であり、対照群に対し有意な差がなかった。また、その耳介厚抑制率は、後述する比較例５の耳介厚抑制率３７．２±５．７％のプラスマイナス５％の範囲外であり、副腎皮質ステロイド外用薬並みの治療効果がなかった。結果を表１に示した。
(Comparative Example 1)
Ointment 2 was obtained by repeating exactly the same preparation method as in Example 1, except that R-flurbiprofen was changed to (2RS) -2- (3-Benzophenyl) propanoic acid (ketoprofen) in Example 1. . The obtained ointment 2 was subjected to an atopic dermatitis suppression test according to Test Example 1. As a result, the pinna thickness suppression rate was -10.8 ± 6.4%, which was not significantly different from the control group. It was. In addition, the pinna thickness suppression rate is outside the range of plus or minus 5% of the pinna thickness suppression rate 37.2 ± 5.7% of Comparative Example 5 to be described later, and the therapeutic effect similar to that of a topical corticosteroid is obtained. There wasn't. The results are shown in Table 1.
（比較例２）
実施例１において、Ｒ−フルルビプロフェンをＭｏｎｏｓｏｄｉｕｍ ２−｛４［（２−ｏｘｏｃｙｃｌｏｐｅｎｔｙｌ）ｍｅｔｈｙｌ］ｐｈｅｎｙｌ｝ｐｒｏｐａｎｏａｔｅ ｄｉｈｙｄｒａｔｅ（ロキソプロフェンナトリウム二水和物）にした以外は実施例１と全く同じ調製法を繰り返して、軟膏剤３を得た。得られた軟膏剤３を試験例１に従ってアトピー性皮膚炎抑制試験を行った結果、耳介厚抑制率は、４．３±６．８％であり、対照群に対し有意な差がなかった。また、その耳介厚抑制率は、後述する比較例５の耳介厚抑制率３７．２±５．７％のプラスマイナス５％の範囲外であり、副腎皮質ステロイド外用薬並みの治療効果がなかった。結果を表１に示した。
(Comparative Example 2)
The same preparation method as in Example 1 except that R-flurbiprofen in Example 1 was changed to Monosodium 2- {4 [(2-oxocyclopentyl) methyl] phenyl} propanoate dihydrate (loxoprofen sodium dihydrate). The ointment 3 was obtained by repeating. The obtained ointment 3 was subjected to an atopic dermatitis suppression test according to Test Example 1. As a result, the auricle thickness suppression rate was 4.3 ± 6.8%, which was not significantly different from the control group. . In addition, the pinna thickness suppression rate is outside the range of plus or minus 5% of the pinna thickness suppression rate 37.2 ± 5.7% of Comparative Example 5 to be described later, and the therapeutic effect similar to that of a topical corticosteroid is obtained. There wasn't. The results are shown in Table 1.
（比較例３）
実施例１において、Ｒ−フルルビプロフェンを（２ＲＳ）−２−（２−Ｆｌｕｏｒｏｂｉｐｈｅｎｙｌ−４−ｙｌ）ｐｒｏｐａｎｏｉｃ ａｃｉｄ（フルルビプロフェン）にした以外は実施例１と全く同じ調製法を繰り返して、軟膏剤４を得た。得られた軟膏剤４を試験例１に従ってアトピー性皮膚炎抑制試験を行った結果、耳介厚抑制率は、８．９±５．１％であり、対照群に対し有意な差がなかった。また、その耳介厚抑制率は、後述する比較例５の耳介厚抑制率３７．２±５．７％のプラスマイナス５％の範囲外であり、副腎皮質ステロイド外用薬並みの治療効果がなかった。結果を表１に示した。
(Comparative Example 3)
In Example 1, exactly the same preparation method as Example 1 was repeated except that R-flurbiprofen was changed to (2RS) -2- (2-Fluorobiphenyl-4-yl) propanoic acid (flurbiprofen). An ointment 4 was obtained. The obtained ointment 4 was subjected to an atopic dermatitis suppression test according to Test Example 1. As a result, the pinna thickness suppression rate was 8.9 ± 5.1%, which was not significantly different from the control group. . In addition, the pinna thickness suppression rate is outside the range of plus or minus 5% of the pinna thickness suppression rate 37.2 ± 5.7% of Comparative Example 5 to be described later, and the therapeutic effect similar to that of a topical corticosteroid is obtained. There wasn't. The results are shown in Table 1.
（比較例４）
実施例１において、Ｒ−フルルビプロフェンを（２Ｓ）−２−（２−Ｆｌｕｏｒｏｂｉｐｈｅｎｙｌ−４−ｙｌ）ｐｒｏｐａｎｏｉｃ ａｃｉｄ（Ｓ−フルルビプロフェン）にした以外は実施例１と全く同じ調製法を繰り返して、軟膏剤５を得た。得られた軟膏剤５を試験例１に従ってアトピー性皮膚炎抑制試験を行った結果、耳介厚抑制率は、０．５±５．５％であり、対照群に対し有意な差がなかった。また、その耳介厚抑制率は、後述する比較例５の耳介厚抑制率３７．２±５．７％のプラスマイナス５％の範囲外であり、副腎皮質ステロイド外用薬並みの治療効果がなかった。結果を表１に示した。
(Comparative Example 4)
The same preparation method as in Example 1 except that R-flurbiprofen was changed to (2S) -2- (2-Fluorobiphenyl-4-yl) propanoic acid (S-flurbiprofen) in Example 1. The ointment 5 was obtained by repeating. The obtained ointment 5 was subjected to an atopic dermatitis suppression test according to Test Example 1. As a result, the pinna thickness suppression rate was 0.5 ± 5.5%, which was not significantly different from the control group. . In addition, the pinna thickness suppression rate is outside the range of plus or minus 5% of the pinna thickness suppression rate 37.2 ± 5.7% of Comparative Example 5 to be described later, and the therapeutic effect similar to that of a topical corticosteroid is obtained. There wasn't. The results are shown in Table 1.
（比較例５）
実施例１において、Ｒ−フルルビプロフェン（１．５ｇ）を９−Ｆｌｕｏｒｏ−１１β，１７，２１−ｔｒｉｈｙｄｒｏｘｙ−１６β−ｍｅｔｈｙｌｐｒｅｇｎａ−１，４−ｄｉｅｎｅ−３，２０−ｄｉｏｎｅ １７−ｐｅｎｔａｎｏａｔｅ（吉草酸ベタメタゾン）（０．０６ｇ）にし、白色ワセリンを４８．５ｇから４９．９４ｇにした以外は実施例１と全く同じ調製法を繰り返して、軟膏剤６を得た。得られた軟膏剤６を試験例１に従ってアトピー性皮膚炎抑制試験を行った結果、耳介厚抑制率は、３７．２±５．７％であり、対照群に対し有意な差があった。また、試験例２に従って１４日間反復経皮投与毒性試験を行った結果、適用皮膚の病理所見において「上皮の壊死」は「＋：軽度」、「真皮の壊死」は「＋＋：中等度」であり、皮膚厚抑制率も２８.９±６.５％と皮膚厚が有意に減少する皮膚委縮があり、皮膚への副作用があった。結果を表１に示した。
(Comparative Example 5)
In Example 1, R-flurbiprofen (1.5 g) was added to 9-Fluoro-11β, 17,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione 17-pentanoate (valeric acid). The same preparation method as Example 1 was repeated except that betamethasone) (0.06 g) and white petrolatum was changed from 48.5 g to 49.94 g to obtain an ointment 6. The obtained ointment 6 was subjected to an atopic dermatitis suppression test according to Test Example 1. As a result, the auricle thickness suppression rate was 37.2 ± 5.7%, which was significantly different from the control group. . In addition, as a result of a 14-day repeated dermal administration toxicity test according to Test Example 2, in the pathological findings of the applied skin, “epithelial necrosis” was “+: mild” and “dermal necrosis” was “++: moderate”. There was a skin atrophy in which the skin thickness was significantly reduced to 28.9 ± 6.5%, and there was a side effect on the skin. The results are shown in Table 1.
本発明は、副腎皮質ステロイド外用薬並みの治療効果があり、なおかつ皮膚への副作用の少ないアトピー性皮膚炎治療薬に関するものであって、産業上十分に利用できるものである。
The present invention relates to a therapeutic agent for atopic dermatitis that has therapeutic effects similar to those of topical corticosteroids and has few side effects on the skin, and can be used sufficiently industrially.
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| EP2468270A1 (en) * | 2010-12-21 | 2012-06-27 | GALENpharma GmbH | (R)-2-(3-fluoro-4-phenylphenyl)propionic acid for use in the treatment of skin diseases |
| WO2013026772A1 (en) * | 2011-08-19 | 2013-02-28 | Johann Wolfgang Goethe-Universität | Flurbiprofen and related compounds for the treatment of skin diseases |
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| EP2468270A1 (en) * | 2010-12-21 | 2012-06-27 | GALENpharma GmbH | (R)-2-(3-fluoro-4-phenylphenyl)propionic acid for use in the treatment of skin diseases |
| WO2013026772A1 (en) * | 2011-08-19 | 2013-02-28 | Johann Wolfgang Goethe-Universität | Flurbiprofen and related compounds for the treatment of skin diseases |
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