JP3979689B2 - Acetylsalicylic acid-containing skin injury treatment agent - Google Patents
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Description
【０００１】
【発明の属する技術分野】
本発明はアセチルサリチル酸を含有する皮膚損傷治療剤に関する。
【０００２】
【従来の技術および発明が解決しようとする課題】
アセチルサリチル酸は一般的にはアスピリンと呼称され、その強力な鎮痛作用と緩和な解熱作用及び抗リウマチ作用により、頭痛薬等に広く使用されている。一方、慢性的な服用で消化性潰瘍を起こす作用やアスピリン喘息を招くことがあり、胃潰瘍における動物病態モデルにアスピリン潰瘍が広く用いられているのもまた事実である。更にサリチル酸誘導体には消炎鎮痛作用を持つ物が多く存在し、これらは外用剤として打ち身、捻挫等に適用されている。このように、医療分野で多量に使用されているアセチルサリチル酸ではあるが、その粘膜上皮傷害作用のためか、創傷に適応することは過去においてなかった。
【０００３】
一方、皮膚損傷は皮膚の創傷であり、創傷の発生原因は物理的によるもの（熱傷、擦過傷、裂傷）が主であるが、現在、その難治性のため注目されている褥瘡を例に取り、その治療方法についての現状を見ると、治療方法としては対症療法が主であり、褥瘡の発生原因の除去や創面の洗浄、消毒、肉芽や表皮の形成環境の整備といった面が主流である。肉芽や表皮組織の形成を積極的に加速する薬物には幼牛血液抽出物（商品名ソルコセリル）、ブグラデシンナトリウム、トレチノイントコフェリル等が開発されているものの、それらの効果は充分とはいえないため、完治を見ない例が数多く存在するのが現状である。従って、難治性の褥瘡に対しても治癒を促進させ得る、作用の強い薬剤の出現が望まれていた。
【０００４】
【課題を解決するための手段】
本発明者等はかかる現況において、表皮組織の形成を強力に促進する化合物を検索するべく研究を行ってきたが、アセチルサリチル酸がこの目的に完全に合致するものであることを見いだし、本発明を完成した。
すなわち、本発明はアセチルサリチル酸を活性成分として含有することを特徴とする皮膚損傷治療剤を提供するものである。
【０００５】
本発明者等は、アセチルサリチル酸を０.１〜１０％濃度含有する局所適用製剤を作成し、この製剤を皮膚損傷部位、具体的にはラットを用いた褥瘡モデル、熱傷・火傷モデルに適用したところ、種々の皮膚損傷状態において、顕著に組織修復の促進傾向が認められ、筋層に達する深い皮膚損傷状態においても痂皮の形成を抑制し肉芽組織の形成及び表皮形成を促進することを見いだした。更に、ラットを用いた皮膚欠損症モデルに対してアセチルサリチル酸を１５ｍｇないしは７５ｍｇ／ｋｇ／日の投与量で経口投与した場合にも、局所適用製剤と同様の効果を見いだした。また、ヒトにおける難治性の褥瘡に上記の局所適用製剤を用いたところ、ほとんどすべての例で創面面積の縮小更には治癒が認められ、この効果は驚くべきものであった。熱傷・火傷についてもアセチルサリチル酸の既知の作用である鎮痛効果の他に皮膚損傷の著明な改善が得られ、この作用は皮膚の損傷全般に適用できうることが見いだされた。
【０００６】
【発明の実施の形態】
上記作用は、局所適用製剤の場合、製剤中のアセチルサリチル酸濃度に依存するため、１５％を超える濃度の製剤ではかえって悪化傾向を示し、０.０５％未満の濃度の製剤においては効果が見られない。したがって、局所適用製剤中のアセチルサリチル酸の含量は０.０５〜１５重量％、好ましくは０.１〜１０重量％、最も好ましくは０.２〜８重量％の範囲である。また、経口投与の場合にも至適投与量が存在し、高用量では悪化傾向を示し、低用量では効果がみられない。したがって、本発明のアセチルサリチル酸の経口投与での有効投与量は、１５〜７５ｍｇ／ｋｇ体重／日、好ましくは２０〜６５ｍｇ／ｋｇ体重／日、最も好ましくは３０〜６０ｍｇ／ｋｇ体重／日である。
【０００７】
本発明の皮膚損傷治療剤は、いずれの投与剤型も採用され、局所適用製剤としては例えば軟膏剤、クリーム剤、ゲル剤、ゲル軟膏剤、貼付剤、液剤、散剤等の剤形を用いることができ、経口製剤としては錠剤、丸剤、カプセル剤、散剤、顆粒剤、細粒剤、ドライシロップ剤等の剤形を用いることができる。
上記製剤の調製は常法により、通常の賦形剤、希釈剤、担体等を用いて行うことができる。
【０００８】
例えば、軟膏剤の調製には、ワセリン、高級アルコール類、ミツロウ、植物油、ポリエチレングリコール等を用いる。市販の軟膏基剤、例えば「プラスチベース」を用いるのが好都合である。クリーム剤の調製には、油脂類、ワックス類、高級脂肪酸類、高級アルコール類、脂肪酸エステル類、精製水、乳化剤などが用いられる。
ゲル剤の調製には、ポリアクリル酸（ポリアクリル酸ナトリウム等）、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルアルコール、ポリビニルピロリドン、精製水、低級アルコール、多価アルコール、ポリエチレングリコールなどが用いられる。
ゲル軟膏剤の調製には、上記ゲル剤に用いられる基剤に加えて、乳化剤（好ましくは非イオン活性剤）、油類（液体パラフィン等）が用いられる。
局所適用製剤には、さらに、パラフィン類、スクワラン、ラノリン、コレステロールエステルなどを配合してもよく、またＢＨＡ、ＢＨＴなどの抗酸化剤なども適宜配合される。
【０００９】
錠剤の調製には、例えば乳糖、白糖、デンプン、炭酸カルシウム、カオリン、結晶セルロースなどの賦形剤、水、単シロップ、ブドウ糖液、デンプン液、ゼラチン溶液、カルボキシメチルセルロース、セラック、メチルセルロース、ポリビニルピロリドンなどの結合剤、乾燥デンプン、アルギン酸ナトリウム、カンテン末、カルメロース、ポリオキシエチレンソルビタン脂肪酸エステル類、ラウリル硫酸ナトリウム、ステアリン酸モノグリセリドなどの崩壊剤、白糖、ステアリン、カカオバター、水素添加油などの崩壊抑制剤、グリセリン、プロピレングリコールなどの保湿剤、デンプン、乳糖、ベントナイト、コロイドケイ酸などの吸着剤、精製タルク、ステアリン酸塩、硫酸カルシウムなどの滑沢剤などが用いられる。さらに錠剤は糖衣錠、ゼラチン被包錠、腸溶被錠、フィルムコーティング錠あるいは二重錠、多層錠とすることができる。
【００１０】
丸剤の調製には、ブドウ糖、乳糖、デンプン、カカオ脂、硬化植物油、カオリン、タルクなどの賦形剤、アラビアゴム末、トラガント末、ゼラチン、セタノールなどの結合剤、ラミナラン、カンテンなどの崩壊剤などが用いられる。
顆粒剤および細粒剤は、上記賦形剤、結合剤などを用い、常法により顆粒化または細粒化して調製される。
またカプセル剤は、アセチルサリチル酸と上記担体類の混合物、好ましくは顆粒、細粒または粉末の形態にて常法により硬カプセルまたは軟カプセルに充填して調製される。
【００１１】
上記経口製剤では活性成分のアセチルサリチル酸の含量は製剤形によっても異なるが、錠剤、顆粒剤、細粒剤、散剤などの固形製剤では、製剤全重量当たり、３０〜７０重量％、好ましくは４０〜６０重量％であり、シロップ剤のような液剤では、製剤全重量当たり、０.１〜１０重量％、好ましくは０.５〜５重量％である。
【００１２】
【実施例】
つぎに、実施例および試験例を用いて本発明をさらに詳しく説明するが、本発明はこれらに限られるものではない。
実施例１ 下記に示す組成に従って、アセチルサリチル酸を少量のエタノールに溶解した後、溶媒を揮散して微粉末とし、これに界面活性剤を加えて均一に混和した。これに軟膏基剤を加えて更に混和し、軟膏剤を得た。
実施例２ 下記に示す組成に従って、実施例１と同様に操作し、軟膏剤を得た。
実施例３ 下記に示す組成に従って、実施例１と同様に操作し、軟膏剤を得た。
実施例４ 下記に示す組成に従って、実施例１と同様に操作し、軟膏剤を得た。
実施例５ 下記に示す組成に従って、実施例１と同様に操作し、軟膏剤を得た。
実施例６ 下記に示す組成に従って、実施例１と同様に操作し、軟膏剤を得た。
実施例７ 下記に示す組成に従って、実施例１と同様に操作し、軟膏剤を得た。
実施例８ 下記に示す組成に従って、実施例１と同様に操作し、軟膏剤を得た。
実施例９ 下記に示す組成に従って、グリセリンにポリアクリル酸ナトリウムを均一に分散し、これに水を加えて、透明なゲル状になるまで撹拌した。続いて、アセチルサリチル酸をプロピレングリコールに均一分散した液をこのゲル状物に加えて撹拌混合し、更に水酸化アルミニウムの懸濁液に乳酸を加えたものを加えて撹拌混合してゲルを得た。このゲルを布上に展延し、表面をプラスチックフィルムで覆った後、適当なサイズに裁断して貼付剤を得た。
実施例１０ 下記に示す組成に従って、ポリアクリル酸ナトリウムをグリセリンに均一分散した後加熱し、透明なゲル状になるまで撹拌した。これにアセチルサリチル酸をプロピレングリコールに均一分散した懸濁液を加えて撹拌混合し、更にみょうばんをグリセリンに均一分散した懸濁液を加えて撹拌混合した。こうして得たゲルを、布上に展延し、表面をプラスチックフィルムで覆った後、適当なサイズに裁断して貼付剤を得た。
実施例１１ 下記に示す組成に従って、アセチルサリチル酸とコーンスターチ、結晶セルロースおよび乳糖を混合し、１０％ヒドロキシプロピルセルロース水溶液５４ｇを加えて練合し、常法に従って、０.７ｍｍ孔あきスクリーンより押し出し造粒し、乾燥、破砕整粒してアスピリン顆粒剤を得た。
実施例１２ 実施例１１で得た顆粒剤４９０ｇにタルク１０ｇを加えて混合し、常法に従って、打錠機を用いて圧縮成形し、１錠当たり０.５ｇ重量を持つアスピリン錠剤を得た。
【００２４】
実施例１３ 下記に示す組成に従って、アセチルサリチル酸を精製水に溶解し、単シロップを加えた後精製水を加えて全量を調整し、水剤を得た。
実施例１４ 下記に示す組成に従って、アセチルサリチル酸を少量のエタノールに溶解した後、溶媒を揮散して微粉末とし、これに軟膏基剤を加えて均一に混和し、軟膏剤を得た。
実施例１５ 下記に示す組成に従って、実施例１４と同様に操作し、軟膏剤を得た。
実施例１６ 下記に示す組成に従って、実施例１４と同様に操作し、軟膏剤を得た。
本発明に従うアセチルサリチル酸含有製剤の驚異的に有利な作用は例えば下記試験例に示すデータから明らかである。
試験例１ ラット褥瘡モデルに対する局所適用したアセチルサリチル酸の作用
体重４００ｇ〜４５０ｇのウィスターラットを１群５匹で本試験に用いた。ラット右大腿部を除毛後ペントバルビタール麻酔下、大腿部に１ｋｇ／ｃｍ2の圧力がかかるように円筒で１日６時間で６日間圧迫し、褥瘡を作成した。
薬剤投与は、褥瘡作成後１日目より１日１回アセチルサリチル酸０.２ｍｇ／部位、０.５ｍｇ／部位、１ｍｇ／部位、２ｍｇ／部位、４ｍｇ／部位の投与量で１４日間行った。効果判定は創傷部の長短径を測定して面積を求め、創傷部位の面積変化を下記式により算出して面積変化曲線を作成し、この面積変化曲線の曲線下面積を算出し指標とした。また、対照薬としてはソルコセリル（商品名）を用いた。その結果を図１に示す。図から明らかなように、アセチルサリチル酸を０.５ｍｇ／部位および１ｍｇ／部位適用した場合に顕著な治癒作用を有することがわかる。
試験例２ ラット欠損傷モデルに対する局所適用したアセチルサリチル酸の作用体重４００ｇ〜４５０ｇのウィスターラットを１群６匹で本試験に用いた。ラット背部を除毛後消毒用イソジンで消毒し、エーテル麻酔下ラット背部皮膚を内径１２ｍｍの円形ポンチで打ち抜き、正中線に対称に２カ所の創傷を作成した。創傷作成１日後よりアセチルサリチル酸を０.５ｍｇ／部位、１ｍｇ／部位、２ｍｇ／部位の投与量で１日１回１４日間投与した。効果判定は創傷部の長短径を測定して面積を求め、創傷部位の面積変化曲線を作成し、この面積変化曲線の曲線下面積を試験例１と同様にして算出し指標とした。また、対照薬としてはソルコセリル（商品名）を用いた。その結果を図２に示す。図から明らかなように、アセチルサリチル酸を０.５ｍｇ／部位、１ｍｇ／部位および２ｍｇ／部位適用した場合に顕著な治癒作用を有することがわかる。
【００３０】
試験例３ ラット熱傷モデルに対する局所適用したアセチルサリチル酸の作用
体重４００〜４５０ｇのウィスター ラットを１群６匹で用いた。ラット背部を除毛後消毒用イソジンで消毒し、エーテル麻酔下、背部皮膚に２００℃の焼きごてを５秒間接触させて熱傷を作成した。作成１日後より熱傷部位にアセチルサリチル酸を１ｍｇ／部位、２ｍｇ／部位の投与量で１日１回１７日間投与した。効果判定は熱傷部の長短径を測定して面積を求め、熱傷部位の面積変化曲線を作成し、この面積変化曲線の曲線下面積を試験例１と同様にして算出し指標とした。また、対照薬としてはソルコセリル（商品名）を用いた。その結果を図３に示す。図から明らかなように、１ｍｇ／部位および２ｍｇ／部位においてアセチルサリチル酸が顕著な治癒作用を有することがわかる。
【００３１】
試験例４ ラット欠損症モデルに対するアセチルサリチル酸の経口投与での作用体重４００〜４５０ｇのウィスターラットを１群５匹で本試験に用いた。ラット背部を除毛後消毒用イソジンで消毒し、エーテル麻酔下ラット背部皮膚を内径１２ｍｍの円形ポンチで打ち抜き、正中線に対称に２カ所の創傷を作成した。創傷作成１日後よりアセチルサリチル酸を１５ｍｇ／ｋｇ／日、３０ｍｇ／ｋｇ／日、６０ｍｇ／ｋｇ／日の投与量で１日１回１３日間投与した。効果判定は創傷部の長短径を測定して面積を求め、創傷部位の面積変化曲線を作成し、この面積変化曲線の曲線下面積を試験例１と同様にして算出し指標とした。その結果を図４に示す。図から明らかなように、３０ｍｇ／ｋｇ／日、６０ｍｇ／ｋｇ／日においてアセチルサリチル酸が顕著な治癒作用を有することがわかる。
【００３２】
試験例５ ヒト褥瘡における効果
アセチルサリチル酸を０.５重量％含有する軟膏製剤を用い、従来の治療薬及び治療方法では治癒の見られなかった難治性の褥瘡に対する治療効果を患者７名の９部位に１ないし２週間投与し、著効、有効、やや有効、無効の４段階で評価した結果、著効５例、有効２例、やや有効１例、無効１例であった。やや有効及び無効例はポケットを有する難治性褥瘡であり、本軟膏は解放性の創に対して著効を示すことが判明した。
【００３３】
試験例６ ラット欠損症モデルに対するアセチルサリチル酸含有軟膏製剤の作用体重３００〜３５０ｇのウィスターラットを１群５匹で本試験に用いた。ラット背部を除毛後消毒用イソジンで消毒し、エーテル麻酔下ラット背部皮膚を内径１０ｍｍの円形ポンチで打ち抜き、正中線に対称に２カ所の創傷を作成した。創傷作成１日後より、実施例１４、１５および１６で作製した軟膏製剤を０.２ｇ／部位の投与量（アセチルサリチル酸として４ｍｇ／部位、８ｍｇ／部位、および１６ｍｇ／部位）で１日１回１４日間投与した。効果判定は創傷部の長短径を測定して面積を求め、創傷部位の面積変化曲線を作成し、この面積変化曲線の曲線下面積を試験例１と同様にして算出し指標とした。その結果を図５に示す。図から明らかなように、アセチルサリチル酸２％、４％および８％含有軟膏製剤の適用により、顕著な治癒作用を有することがわかる。
【００３４】
【発明の効果】
本発明により、これまで非常に治療が困難であった褥瘡についての治癒が期待できる。更に、熱傷、皮膚欠損症等についても治癒の促進が期待できる等の効果を有する。
【図面の簡単な説明】
【図１】 ラットの褥瘡モデルに対する局所適用したアセチルサリチル酸の作用を示す棒グラフである。
【図２】 ラット欠損傷モデルに対する局所適用したアセチルサリチル酸の作用を示す棒グラフである。
【図３】 ラットの熱傷モデルに対する局所適用したアセチルサリチル酸の作用を示す棒グラフである。
【図４】 ラット欠損症モデルに対する経口投与したアセチルサリチル酸の作用を示す棒グラフである。
【図５】 ラット欠損症モデルに対するアセチルサリチル酸含有軟膏製剤の作用を示す棒グラフである。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a skin injury therapeutic agent containing acetylsalicylic acid.
[0002]
[Background Art and Problems to be Solved by the Invention]
Acetylsalicylic acid is generally called aspirin, and is widely used for headache drugs and the like due to its powerful analgesic action, mild antipyretic action and antirheumatic action. On the other hand, the effect of causing peptic ulcer and aspirin asthma may be caused by chronic use, and it is also true that aspirin ulcer is widely used in animal pathological models in gastric ulcer. In addition, many salicylic acid derivatives have anti-inflammatory and analgesic effects, and these are applied to bruises, sprains and the like as external preparations. Thus, although it is acetylsalicylic acid used in large quantities in the medical field, it has not been applied to wounds in the past because of its mucosal epithelial damage action.
[0003]
On the other hand, skin damage is a skin wound, and the cause of the wound is mainly due to physical damage (burn, abrasion, laceration), but taking pressure ulcers that are currently attracting attention due to its intractability, Looking at the current state of treatment methods, symptomatic treatment is the main treatment method, and removal of the cause of pressure ulcers, cleaning of the wound surface, disinfection, and maintenance of the formation environment for granulation and epidermis are the mainstream. Although calf blood extract (trade name solcoseryl), bugradesin sodium, tretinoin tocopheryl, and the like have been developed as drugs that actively accelerate the formation of granulation and epidermal tissue, their effects are sufficient. Since there is no such thing, there are many examples that do not see complete cure. Therefore, it has been desired to develop a drug having a strong action that can promote healing even for intractable pressure ulcers.
[0004]
[Means for Solving the Problems]
In the present situation, the present inventors have conducted research to search for a compound that strongly promotes the formation of epidermal tissue, but found that acetylsalicylic acid perfectly meets this purpose. completed.
That is, the present invention provides a therapeutic agent for skin damage characterized by containing acetylsalicylic acid as an active ingredient.
[0005]
The present inventors made a topical preparation containing 0.1 to 10% concentration of acetylsalicylic acid, and applied this preparation to a skin damage site, specifically, a pressure ulcer model using rats and a burn / burn model. However, in various skin damage states, a tendency to promote tissue repair was recognized, and it was found that formation of granulation tissue and epidermis was promoted by suppressing crust formation even in deep skin damage reaching the muscle layer. It was. Further, when acetylsalicylic acid was orally administered at a dose of 15 mg to 75 mg / kg / day for a skin defect model using rats, the same effect as that of the topical preparation was found. In addition, when the above-mentioned topical preparation was used for intractable pressure ulcers in humans, almost all cases showed reduction in wound area and further healing, and this effect was surprising. Regarding burns and burns, in addition to the analgesic effect, which is a known action of acetylsalicylic acid, a significant improvement in skin damage was obtained, and it was found that this action can be applied to general skin damage.
[0006]
DETAILED DESCRIPTION OF THE INVENTION
The above-mentioned action depends on the acetylsalicylic acid concentration in the preparation in the case of a topical preparation, and thus shows a worsening tendency with a preparation with a concentration of more than 15%, and an effect is seen with a preparation with a concentration of less than 0.05% Absent. Accordingly, the content of acetylsalicylic acid in the topical preparation is in the range of 0.05 to 15% by weight, preferably 0.1 to 10% by weight, most preferably 0.2 to 8% by weight. In the case of oral administration, there is an optimum dose, which shows a tendency to deteriorate at a high dose and has no effect at a low dose. Accordingly, the effective dosage of oral acetylsalicylic acid of the present invention is 15 to 75 mg / kg body weight / day, preferably 20 to 65 mg / kg body weight / day, and most preferably 30 to 60 mg / kg body weight / day. .
[0007]
Any dosage form may be employed as the skin injury treatment agent of the present invention, and for example, dosage forms such as ointments, creams, gels, gel ointments, patches, liquids, powders and the like are used as topical preparations. As oral preparations, dosage forms such as tablets, pills, capsules, powders, granules, fine granules, and dry syrups can be used.
The above preparation can be prepared by a conventional method using ordinary excipients, diluents, carriers and the like.
[0008]
For example, petrolatum, higher alcohols, beeswax, vegetable oil, polyethylene glycol and the like are used for the preparation of an ointment. It is convenient to use a commercially available ointment base such as “Plastibase”. For the preparation of the cream, fats and oils, waxes, higher fatty acids, higher alcohols, fatty acid esters, purified water, emulsifiers and the like are used.
For the preparation of the gel, polyacrylic acid (such as sodium polyacrylate), hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, purified water, lower alcohol, polyhydric alcohol, polyethylene glycol and the like are used.
In preparation of the gel ointment, an emulsifier (preferably a nonionic active agent) and oils (liquid paraffin or the like) are used in addition to the base used in the gel.
The topical preparation may further contain paraffins, squalane, lanolin, cholesterol esters and the like, and antioxidants such as BHA and BHT are also appropriately blended.
[0009]
For tablet preparation, for example, excipients such as lactose, sucrose, starch, calcium carbonate, kaolin, crystalline cellulose, water, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, polyvinylpyrrolidone, etc. Binders, dry starch, sodium alginate, agar powder, carmellose, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglycerides of stearic acid, disintegrators such as sucrose, stearin, cacao butter, hydrogenated oil Moisturizers such as glycerin and propylene glycol, adsorbents such as starch, lactose, bentonite and colloidal silicic acid, and lubricants such as purified talc, stearate and calcium sulfate are used. Furthermore, the tablets can be sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets.
[0010]
For the preparation of pills, excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, talc, binders such as gum arabic powder, tragacanth powder, gelatin, cetanol, disintegrants such as laminaran, agar Etc. are used.
Granules and fine granules are prepared by granulation or fine granulation by a conventional method using the above-mentioned excipients and binders.
Capsules are prepared by filling hard capsules or soft capsules by a conventional method in the form of a mixture of acetylsalicylic acid and the above carriers, preferably in the form of granules, fine granules or powder.
[0011]
In the above oral preparation, the content of the active ingredient acetylsalicylic acid varies depending on the preparation form, but in the case of solid preparations such as tablets, granules, fine granules and powders, 30 to 70% by weight, preferably 40 to 40%, based on the total weight of the preparation. 60% by weight, and in the case of a solution such as a syrup, it is 0.1 to 10% by weight, preferably 0.5 to 5% by weight, based on the total weight of the preparation.
[0012]
【Example】
Next, the present invention will be described in more detail using examples and test examples, but the present invention is not limited to these examples.
Example 1 According to the composition shown below, acetylsalicylic acid was dissolved in a small amount of ethanol, and then the solvent was stripped to form a fine powder, and a surfactant was added thereto and mixed uniformly. An ointment base was added thereto and further mixed to obtain an ointment.
Example 2 An ointment was obtained in the same manner as in Example 1 according to the composition shown below.
Example 3 According to the composition shown below, the same procedure as in Example 1 was followed to obtain an ointment.
Example 4 According to the composition shown below, the same procedure as in Example 1 was followed to obtain an ointment.
Example 5 According to the composition shown below, the same procedure as in Example 1 was followed to obtain an ointment.
Example 6 According to the composition shown below, the same operation as in Example 1 was performed to obtain an ointment.
Example 7 According to the composition shown below, the same procedure as in Example 1 was followed to obtain an ointment.
Example 8 According to the composition shown below, the same procedure as in Example 1 was followed to obtain an ointment.
Example 9 According to the composition shown below, sodium polyacrylate was uniformly dispersed in glycerin, water was added thereto, and the mixture was stirred until it became a transparent gel. Subsequently, a solution in which acetylsalicylic acid was uniformly dispersed in propylene glycol was added to the gel-like material and mixed by stirring. Further, a suspension obtained by adding lactic acid to a suspension of aluminum hydroxide was added and mixed by stirring to obtain a gel. . This gel was spread on a cloth, and the surface was covered with a plastic film, and then cut into an appropriate size to obtain a patch.
Example 10 According to the composition shown below, sodium polyacrylate was uniformly dispersed in glycerin and then heated and stirred until it became a transparent gel. To this, a suspension in which acetylsalicylic acid was uniformly dispersed in propylene glycol was added and mixed by stirring. Further, a suspension in which alum was uniformly dispersed in glycerin was added and mixed by stirring. The gel thus obtained was spread on a cloth and the surface was covered with a plastic film, and then cut into an appropriate size to obtain a patch.
Example 11 According to the composition shown below, acetylsalicylic acid, corn starch, crystalline cellulose and lactose were mixed, kneaded by adding 54 g of a 10% hydroxypropylcellulose aqueous solution, and extruded and granulated from a 0.7 mm perforated screen according to a conventional method. Then, it was dried and crushed and sized to obtain aspirin granules.
Example 12 10 g of talc was added to and mixed with 490 g of the granule obtained in Example 11, and compression-molded using a tableting machine according to a conventional method to obtain an aspirin tablet having a weight of 0.5 g per tablet.
[0024]
Example 13 According to the composition shown below, acetylsalicylic acid was dissolved in purified water, simple syrup was added, and then purified water was added to adjust the total amount to obtain a liquid medicine.
Example 14 According to the composition shown below, acetylsalicylic acid was dissolved in a small amount of ethanol, and then the solvent was stripped to form a fine powder. An ointment base was added thereto and mixed uniformly to obtain an ointment.
Example 15 An ointment was obtained in the same manner as in Example 14 according to the composition shown below.
Example 16 According to the composition shown below, the same procedure as in Example 14 was followed to obtain an ointment.
The surprisingly advantageous action of the preparation containing acetylsalicylic acid according to the present invention is apparent from the data shown in the following test examples, for example.
Test Example 1 Action of locally applied acetylsalicylic acid on a rat pressure ulcer model Wistar rats weighing 400 g to 450 g were used in this test with 5 rats per group. Rat right thigh hair removal after pentobarbital anesthesia, in 6 hours a day in the cylinder so that pressure is applied of 1kg / cm 2 in the thigh to compress 6 days, it was to create a pressure ulcer.
The drug administration was carried out for 14 days at a dose of acetylsalicylic acid 0.2 mg / site, 0.5 mg / site, 1 mg / site, 2 mg / site, 4 mg / site once a day from the first day after the pressure ulcer was created. The effect was determined by measuring the major and minor axis of the wound part to determine the area, calculating the area change of the wound site by the following formula, creating an area change curve, and calculating the area under the curve of the area change curve as an index. Moreover, Solcoseryl (trade name) was used as a control drug. The result is shown in FIG. As is apparent from the figure, it can be seen that when acetylsalicylic acid is applied at 0.5 mg / site and 1 mg / site, it has a remarkable healing effect.
Test Example 2 Effect of locally applied acetylsalicylic acid on a rat deficiency injury model Wistar rats weighing 400 to 450 g were used in this test with 6 rats per group. The rat back was disinfected with disinfectant isodine after hair removal, and the rat dorsal skin under ether anesthesia was punched with a circular punch with an inner diameter of 12 mm to create two wounds symmetrically about the midline. Acetylsalicylic acid was administered once a day for 14 days at doses of 0.5 mg / site, 1 mg / site, and 2 mg / site one day after wound creation. The effect was determined by measuring the major and minor diameters of the wound part to determine the area, creating an area change curve of the wound site, and calculating the area under the curve of the area change curve in the same manner as in Test Example 1 as an index. Moreover, Solcoseryl (trade name) was used as a control drug. The result is shown in FIG. As is apparent from the figure, it can be seen that when acetylsalicylic acid is applied at 0.5 mg / site, 1 mg / site and 2 mg / site, it has a remarkable healing effect.
[0030]
Test Example 3 Effect of locally applied acetylsalicylic acid on rat burn model Wistar rats weighing 400 to 450 g were used in groups of 6 rats. The rat's back was disinfected with disinfectant isodine after hair removal, and a burn was created by contacting a 200 ° C. iron on the back skin for 5 seconds under ether anesthesia. One day after the preparation, acetylsalicylic acid was administered to the burn site at a dose of 1 mg / site and 2 mg / site once a day for 17 days. The effect was determined by measuring the major and minor diameters of the burned part to determine the area, creating an area change curve of the burned part, and calculating the area under the curve of the area change curve in the same manner as in Test Example 1 as an index. Moreover, Solcoseryl (trade name) was used as a control drug. The result is shown in FIG. As can be seen from the figure, acetylsalicylic acid has a remarkable healing effect at 1 mg / site and 2 mg / site.
[0031]
Test Example 4 Effect of Oral Administration of Acetylsalicylic Acid on Rat Deficiency Model Wistar rats weighing 400 to 450 g were used in this test for 5 rats per group. The rat back was disinfected with disinfectant isodine after hair removal, and the rat dorsal skin under ether anesthesia was punched with a circular punch with an inner diameter of 12 mm to create two wounds symmetrically about the midline. From 1 day after wound creation, acetylsalicylic acid was administered at a dose of 15 mg / kg / day, 30 mg / kg / day, 60 mg / kg / day once a day for 13 days. The effect was determined by measuring the major and minor diameters of the wound part to determine the area, creating an area change curve of the wound site, and calculating the area under the curve of the area change curve in the same manner as in Test Example 1 as an index. The result is shown in FIG. As is apparent from the figure, it can be seen that acetylsalicylic acid has a remarkable healing action at 30 mg / kg / day and 60 mg / kg / day.
[0032]
Test Example 5 Effect on human pressure ulcers Using an ointment preparation containing 0.5% by weight of acetylsalicylic acid, the therapeutic effect on refractory pressure ulcers that could not be cured by conventional therapeutic agents and treatment methods was demonstrated in 9 sites of 7 patients For 1 to 2 weeks, and evaluated in 4 stages of effective, effective, slightly effective, and ineffective. As a result, there were 5 effective cases, 2 effective cases, 1 effective case, and 1 ineffective case. Slightly effective and ineffective cases are intractable pressure ulcers with pockets, and this ointment was found to be highly effective for releasable wounds.
[0033]
Test Example 6 Effect of Acetyl Salicylic Acid-Containing Ointment Formula on Rat Deficiency Model Wistar rats weighing 300 to 350 g were used in this test with 5 mice per group. The rat back was disinfected with disinfectant isodine after hair removal, and the rat back skin under ether anesthesia was punched with a circular punch having an inner diameter of 10 mm to create two wounds symmetrically with respect to the midline. One day after wound creation, the ointment preparations prepared in Examples 14, 15 and 16 were administered once a day at doses of 0.2 g / site (4 mg / site, 8 mg / site and 16 mg / site as acetylsalicylic acid). Administered for 1 day. The effect was determined by measuring the major and minor diameters of the wound part to determine the area, creating an area change curve of the wound site, and calculating the area under the curve of the area change curve in the same manner as in Test Example 1 as an index. The result is shown in FIG. As is apparent from the figure, it can be seen that application of an ointment preparation containing 2%, 4% and 8% acetylsalicylic acid has a remarkable healing effect.
[0034]
【The invention's effect】
The present invention can be expected to cure pressure ulcers that have been very difficult to treat. Furthermore, it has an effect that healing can be expected for burns, skin defects and the like.
[Brief description of the drawings]
FIG. 1 is a bar graph showing the effect of topically applied acetylsalicylic acid on a rat pressure ulcer model.
FIG. 2 is a bar graph showing the effect of topically applied acetylsalicylic acid on a rat defect model.
FIG. 3 is a bar graph showing the effect of topically applied acetylsalicylic acid on a rat burn model.
FIG. 4 is a bar graph showing the effect of orally administered acetylsalicylic acid on a rat deficiency model.
FIG. 5 is a bar graph showing the effect of an acetylsalicylic acid-containing ointment formulation on a rat deficiency model.
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP34510396A JP3979689B2 (en) | 1995-12-26 | 1996-12-25 | Acetylsalicylic acid-containing skin injury treatment agent |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7-338745 | 1995-12-26 | ||
| JP33874595 | 1995-12-26 | ||
| JP34510396A JP3979689B2 (en) | 1995-12-26 | 1996-12-25 | Acetylsalicylic acid-containing skin injury treatment agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH09235232A JPH09235232A (en) | 1997-09-09 |
| JP3979689B2 true JP3979689B2 (en) | 2007-09-19 |
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| Application Number | Title | Priority Date | Filing Date |
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| JP34510396A Expired - Fee Related JP3979689B2 (en) | 1995-12-26 | 1996-12-25 | Acetylsalicylic acid-containing skin injury treatment agent |
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| JP4729149B2 (en) * | 1997-06-25 | 2011-07-20 | 帝國製薬株式会社 | Stable aspirin ointment formulation |
| JP4868687B2 (en) * | 2002-09-30 | 2012-02-01 | 帝國製薬株式会社 | External preparation for inhibiting formation of keloids |
| US20110098256A1 (en) * | 2009-10-22 | 2011-04-28 | Hines Dixie J | Method for making and using a topical dermatological solution |
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