JP4899139B2 - Antifungal pharmaceutical composition - Google Patents
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- JP4899139B2 JP4899139B2 JP2000241953A JP2000241953A JP4899139B2 JP 4899139 B2 JP4899139 B2 JP 4899139B2 JP 2000241953 A JP2000241953 A JP 2000241953A JP 2000241953 A JP2000241953 A JP 2000241953A JP 4899139 B2 JP4899139 B2 JP 4899139B2
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Description
【0001】
【発明の属する技術分野】
本発明は、抗真菌医薬組成物に関し、更に詳細には、爪白癬症に好適な抗真菌医薬組成物に関する。
【0002】
【従来の技術】
真菌症は、少し前には、「水虫の完全な治療薬を開発すればノーベル賞がもらえる」と言う伝説が存在するほど、完治が困難な疾病であった。真菌症には、大きく分けると、1)指或いは指の間に生ずる皮膚真菌症、2)爪に生ずる爪白癬症及び3)内臓などの深部に発生する、深部真菌症の3種が存在し、この内、皮膚真菌症については、効果に優れるブテナフィンやテルビナフィンなどの新規抗真菌剤の開発により、克服されつつあるが、爪白癬症と深部真菌症については、未だ決定的な手段が見いだされていない。この内、前者に関しては、テルビナフィンの長期経口投与による治療が有効であることが知られているが、長期経口投与による副作用の可能性は低くなく、局所投与での克服手段が求められていた。爪白癬症における局所投与による治療は、今までは、その厚いハードケラチン層に薬剤の浸透が阻まれて、有効性が得られていなかった。又、爪白癬症に使用される局所投与外用剤としてはアモロルフィンの局所投与外用剤が知られているが、このアモロルフィンの局所投与外用剤の爪白癬症への有効性はさほど高くないことが知られている。
【0003】
テルビナフィンは抗真菌剤として知られており、その製造方法も既に公知である。又、エチルセルロースは、医薬品用の皮膜形成剤として既に広く知られている。又、メタアクリル酸・メタアクリル酸メチルコポリマーについても、例えば、「オイドラギットL−100」の名で市販されているものもあるように、医薬用皮膜形成剤である。しかしながら、これらを組み合わせて抗真菌医薬組成物を作成すること、特に、爪白癬症用の医薬組成物を作成することは全く知られていなかった。
【0004】
【発明が解決しようとする課題】
本発明は、この様な状況下為されたものであり、抗真菌症、取り分け爪白癬症に好適な医薬組成物を提供することを課題とする。
【0005】
【課題の解決手段】
本発明者らは、この様な状況に鑑みて、抗真菌症取り分け、爪白癬症に好適な医薬組成物を求め、鋭意研究努力を重ねた結果、1)テルビナフィン及び/又はその塩と2)エチルセルロースとを医薬組成物に含有させることにより、この様な特質を備えた医薬組成物が得られることを見いだし、発明を完成させるに至った。即ち、本発明は、以下に示す技術に関するものである。
(1)1)テルビナフィン及び/又はその塩と2)エチルセルロースとを含有することを特徴とする、抗真菌医薬組成物。
(2)更にメタアクリル酸・メタアクリル酸メチルコポリマー及び/又はその塩を含有することを特徴とする、(1)に記載の抗真菌医薬組成物。
(3)爪白癬症用であることを特徴とする、(1)又は(2)に記載の抗真菌医薬組成物。
(4)皮膚外用剤であることを特徴とする、(1)〜(3)何れか1項に記載の抗真菌医薬組成物。
以下、本発明について、その実施の形態を中心に更に詳細に説明を加える。
【0006】
【発明の実施の形態】
(1)本発明の医薬組成物の必須成分である、エチルセルロース
本発明の医薬組成物は、エチルセルロースを含有することを特徴とする。エチルセルロースは非水溶性の被膜形成剤として、例えば錠剤や顆粒をコーティング目的で使用されるなど、特に医薬品の分野で広く用いられてきたものであり、エチルセルロースでコーティングされた顆粒は腸溶性或いは徐放性を有することが知られている。本発明の医薬組成物においては、皮膚外用剤に適用した場合の,投与部位に於ける皮膜形成剤として好適に使用される。被膜形成剤としてエチルセルロースを唯一種含有させることも出来るし、二種以上を組み合わせて含有させることも出来る。これらのエチルセルロースの好ましい含有量は、皮膚外用剤全量に対して、総量で0.5〜10重量%が好ましく、更に好ましくは1〜5重量%である。これは、少なすぎると、薬物の爪などの生体組織中へ浸透させる作用が得られない場合があり、多すぎても効果が頭打ちになったり、かえって薬物浸透を阻害したりする場合があるからである。
【0007】
(2)本発明の医薬組成物の必須成分であるテルビナフィン及び/又はその塩
本発明の、医薬組成物は上記のエチルセルロース以外に、抗真菌作用の有効成分としてのテルビナフィン及び/又はその塩を含有することを特徴とする。テルビナフィンは既に抗真菌剤と使用されておりその製造方法も既に知られている。即ち、対応するN−メチルアミノナフタレンと1−クロロ−6,6−ジメチルヘプテン−4−インとをアルカリ存在下縮合することにより得ることが出来る。このものの塩としては、ナフタレン環に結合している置換アミノ基と塩を形成するものであれば、特段の限定無く適用でき、例えば、塩酸塩、硝酸塩、硫酸塩等の鉱酸塩、クエン酸塩、シュウ酸塩、コハク酸塩などの有機酸塩などが好ましく例示でき、塩酸塩が特に好ましい。これらは唯一種を含有させることも出来るし、二種以上を組み合わせて含有させることも出来る。本発明の医薬組成物に於けるこれらテルビナフィン及び/又はその塩の好ましい含有量は、医薬組成物全量に対して、総量で0.1〜10重量%であり、更に好ましくは0.5〜7重量%である。
【0008】
(3)本発明の医薬組成物
本発明の医薬組成物は、上記必須成分を含有することを特徴とする。本発明の医薬組成物の投与経路は特段の限定はされないが、その効果より、局所投与、即ち、爪を含めた皮膚外用剤として使用することが好ましい。この様な適用で特に好ましいのは、他に類を見ない効果を発揮する爪であるが、皮膚に於ける浸透性も優れるため、皮膚に適用することも本発明の技術的範囲に属する。本発明の医薬組成物においては、上記必須成分以外に通常医薬組成物で使用される任意成分を含有することが出来る。この様な任意成分としては、例えば、スクワラン、ワセリン、マイクロクリスタリンワックス等の炭化水素類、ホホバ油、カルナウバワックス,オレイン酸オクチルドデシル等のエステル類、オリーブ油、牛脂、椰子油等のトリグリセライド類、ステアリン酸、オレイン酸、リチノレイン酸等の脂肪酸、オレイルアルコール、ステアリルアルコール、オクチルドデカノール等の高級アルコール、スルホコハク酸エステルやポリオキシエチレンアルキル硫酸ナトリウム等のアニオン界面活性剤類、アルキルベタイン塩等の両性界面活性剤類、ジアルキルアンモニウム塩等のカチオン界面活性剤類、ソルビタン脂肪酸エステル、脂肪酸モノグリセライド、これらのポリオキシエチレン付加物、ポリオキシエチレンアルキルエーテル、ポリオキシエチレン脂肪酸エステル等の非イオン界面活性剤類、ポリエチレングリコール、グリセリン、1,3−ブタンジオール等の多価アルコール類、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、メチルセルロース、メタアクリル酸・メタアクリル酸メチルコポリマー、メタアクリル酸エチルメタアクリル酸塩化トリメチルアンモニウムエチルコポリマーなどの被膜形成剤、トリアセチン、フタル酸ジエチル、カプリル酸グリセリル、クエン酸トリエチル、アジピン酸ジエチル、アジピン酸ジイソプロピルなどの可塑剤、増粘・ゲル化剤、酸化防止剤、紫外線吸収剤、色剤、防腐剤、粉体等を好ましく例示できる。これらの内、特に好ましいものは、皮膜特性を好適に変えられるメタアクリル酸・メタアクリル酸メチルコポリマーである。メタアクリル酸・メタアクリル酸メチルコポリマーの好ましい含有量は、0.1〜1重量%であり、更に好ましくは、0.2〜0.8重量%である。これは、多すぎるとかえって、エチルセルロースの被膜特性を損なうことがあり、少なすぎると被膜特性の改良効果が得られない場合があるからである。又、この様な被膜にとって好適な可塑剤はアジピン酸ジイソプロピルであり、その好ましい含有量は、5〜15重量%である。これらの必須成分と任意成分とを常法に従って処理することにより、本発明の医薬組成物は製造することが出来る。
【0009】
【実施例】
以下に、本発明について、実施例を挙げて更に詳細に説明を加えるが、本発明がこの様な実施例にのみ限定されないことは言うまでもない。
【0010】
<実施例1>
以下に示す処方に従って、本発明の医薬組成物を作成した。即ち、処方成分を室温で攪拌可溶化し、本発明の医薬組成物を得た。
エチルセルロース 4 重量部
水 4 重量部
アジピン酸ジイソプロピル 9 重量部
塩酸テルビナフィン 5 重量部
エタノール 78 重量部
<実施例2>
以下に示す処方に従って、本発明の医薬組成物を作成した。即ち、処方成分を室温で攪拌可溶化し、本発明の医薬組成物を得た。
エチルセルロース 3.5重量部
メタアクリル酸・メタアクリル酸メチルコポリマー 0.5重量部
水 4 重量部
アジピン酸ジイソプロピル 9 重量部
塩酸テルビナフィン 5 重量部
エタノール 78 重量部
【0011】
<実施例3>
上記、本発明の皮膚外用剤を用いて、爪白癬モデルに対する作用を調べた。即ち、塩培地1lにバクト・アガー15gを加え、寒天塩培地を作成し、オートクレーブで滅菌後、45℃まで冷却し、スラント培養して得た胞子懸濁液を分生子数を1×106個/mlになるよう調整して加え、90mlのシャーレに2ml静かに分注した。寒天の固化を確認し、シリコーンゴム接着剤でヒトの爪にテフロン製Oリングを接着させたものを培地中央に置き、5日間感染させた。感染後実施例1の医薬組成物5μlをテフロン製Oリング内にチャージした。薬剤添加から経時的に爪と寒天培地の間に生育している菌糸の状態を次に示す基準に従って、目視で観察した。比較例として、実施例2の塩酸テルビナフィンを塩酸アモロルフィンに置換したものを比較例1、クロトリマゾールに置換したものを比較例2とし、同様の操作を行った。4例における平均スコアを表1に示す。これより、本発明の医薬組成物は、爪白癬症に対して卓効があることが明白である。
観察基準;スコア3:菌の増殖が見られた、スコア2:薬剤添加時と変わりなし、スコア1:菌の減少が見られた、スコア0.5:僅かながら菌の存在が見られた、スコア0:菌が陰性化した
【0012】
【表1】
【0013】
【発明の効果】
本発明によれば、抗真菌症取り分け、爪白癬症に好適な医薬組成物を提供することができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an antifungal pharmaceutical composition, and more particularly to an antifungal pharmaceutical composition suitable for onychomycosis.
[0002]
[Prior art]
Mycosis was a disease that was difficult to cure so long ago that there was a legend that if you developed a complete treatment for athlete's foot, you would receive a Nobel Prize. Broadly speaking, there are three types of mycosis: 1) dermatomycosis that occurs between fingers or fingers, 2) onychomycosis that occurs on the nail, and 3) deep mycosis that develops deep in the internal organs. Of these, dermatomycosis is being overcome by the development of new antifungal agents such as butenafine and terbinafine, which are highly effective, but definitive measures have yet been found for onychomycosis and deep mycosis. Not. Among these, for the former, it is known that treatment by long-term oral administration of terbinafine is effective, but the possibility of side effects due to long-term oral administration is not low, and means for overcoming by local administration has been demanded. To date, treatment with topical treatment for onychomycosis has not been effective because the drug penetrates the thick hard keratin layer. As a topical topical preparation for use in onychomycosis, a topical topical application of amorolfine is known. However, it is known that the topical topical application of amorolfine is not very effective for onychomycosis. It has been.
[0003]
Terbinafine is known as an antifungal agent and its production method is already known. Ethyl cellulose is already widely known as a film-forming agent for pharmaceuticals. Further, methacrylic acid / methacrylic acid methyl copolymer is also a film-forming agent for pharmaceuticals, for example, as commercially available under the name “Eudragit L-100”. However, it has not been known at all to produce an antifungal pharmaceutical composition by combining these, particularly to produce a pharmaceutical composition for onychomycosis.
[0004]
[Problems to be solved by the invention]
The present invention has been made under such circumstances, and an object of the present invention is to provide a pharmaceutical composition suitable for antimycosis and, in particular, onychomycosis.
[0005]
[Means for solving problems]
In view of such circumstances, the present inventors have devised diligent research efforts, seeking a pharmaceutical composition suitable for onychomycosis, and intensive research efforts. 1) Terbinafine and / or a salt thereof 2) It has been found that a pharmaceutical composition having such characteristics can be obtained by including ethyl cellulose in the pharmaceutical composition, and the present invention has been completed. That is, this invention relates to the technique shown below.
(1) An antifungal pharmaceutical composition comprising 1) terbinafine and / or a salt thereof and 2) ethylcellulose.
(2) The antifungal pharmaceutical composition according to (1), further comprising a methacrylic acid / methyl methacrylate copolymer and / or a salt thereof.
(3) The antifungal pharmaceutical composition according to (1) or (2), which is for onychomycosis.
(4) The antifungal pharmaceutical composition according to any one of (1) to (3), which is an external preparation for skin.
Hereinafter, the present invention will be described in more detail with a focus on the embodiment thereof.
[0006]
DETAILED DESCRIPTION OF THE INVENTION
(1) Ethylcellulose, which is an essential component of the pharmaceutical composition of the present invention The pharmaceutical composition of the present invention is characterized by containing ethylcellulose. Ethylcellulose has been widely used as a non-water-soluble film-forming agent, for example, for the purpose of coating tablets and granules, particularly in the pharmaceutical field. Granules coated with ethylcellulose are enteric or sustained-release. It is known to have sex. The pharmaceutical composition of the present invention is suitably used as a film-forming agent at the administration site when applied to an external preparation for skin. As a film forming agent, ethyl cellulose can be contained alone or in combination of two or more. The preferable content of these ethyl celluloses is preferably 0.5 to 10% by weight, more preferably 1 to 5% by weight, based on the total amount of the external preparation for skin. This is because if the amount is too small, there may be cases where the action of penetrating the drug into the living tissue such as the nail may not be obtained, and if the amount is too large, the effect may reach its peak or the drug penetration may be inhibited. It is.
[0007]
(2) Terbinafine and / or salt thereof, which is an essential component of the pharmaceutical composition of the present invention The pharmaceutical composition of the present invention contains terbinafine and / or salt thereof as an active ingredient of antifungal action in addition to the above ethyl cellulose. It is characterized by doing. Terbinafine has already been used as an antifungal agent and its production method is already known. That is, it can be obtained by condensing the corresponding N-methylaminonaphthalene and 1-chloro-6,6-dimethylheptene-4-yne in the presence of alkali. As a salt of this, as long as it forms a salt with a substituted amino group bonded to the naphthalene ring, it can be applied without particular limitation. For example, mineral salts such as hydrochloride, nitrate, sulfate, citric acid Organic salts such as salts, oxalates, and succinates can be preferably exemplified, and hydrochlorides are particularly preferable. These can contain only the seed | species, and can also be made to contain in combination of 2 or more type. The preferred content of terbinafine and / or a salt thereof in the pharmaceutical composition of the present invention is 0.1 to 10% by weight, more preferably 0.5 to 7%, based on the total amount of the pharmaceutical composition. % By weight.
[0008]
(3) Pharmaceutical composition of the present invention The pharmaceutical composition of the present invention is characterized by containing the above essential components. Although the administration route of the pharmaceutical composition of the present invention is not particularly limited, it is preferably used as a topical administration, that is, as an external preparation for skin including nails, because of its effect. Particularly preferable for such application is a nail that exhibits an unprecedented effect. However, since it has excellent permeability in the skin, application to the skin is also within the technical scope of the present invention. In the pharmaceutical composition of this invention, the arbitrary component normally used by pharmaceutical composition other than the said essential component can be contained. Such optional components include, for example, hydrocarbons such as squalane, petrolatum, microcrystalline wax, esters such as jojoba oil, carnauba wax, octyldodecyl oleate, triglycerides such as olive oil, beef tallow, coconut oil, Fatty acids such as stearic acid, oleic acid, lithinoleic acid, higher alcohols such as oleyl alcohol, stearyl alcohol, octyldodecanol, anionic surfactants such as sulfosuccinic acid ester and sodium polyoxyethylene alkyl sulfate, and amphoteric compounds such as alkyl betaine salts Surfactants, cationic surfactants such as dialkyl ammonium salts, sorbitan fatty acid esters, fatty acid monoglycerides, polyoxyethylene adducts thereof, polyoxyethylene alkyl ethers, polyoxyethylenes Nonionic surfactants such as len fatty acid esters, polyhydric alcohols such as polyethylene glycol, glycerin, 1,3-butanediol, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, methacrylic acid / methacrylic acid methyl copolymer, Film formers such as ethyl methacrylate methacrylate trimethylammonium ethyl copolymer, plasticizers such as triacetin, diethyl phthalate, glyceryl caprylate, triethyl citrate, diethyl adipate, diisopropyl adipate, thickener / gelling agent Preferred examples include antioxidants, ultraviolet absorbers, colorants, preservatives, and powders. Of these, particularly preferred are methacrylic acid / methyl methacrylate copolymers capable of suitably changing the film properties. The preferred content of the methacrylic acid / methyl methacrylate copolymer is 0.1 to 1% by weight, more preferably 0.2 to 0.8% by weight. This is because if the amount is too large, the film properties of ethyl cellulose may be impaired. If the amount is too small, the effect of improving the film properties may not be obtained. A suitable plasticizer for such a coating is diisopropyl adipate, and its preferred content is 5 to 15% by weight. The pharmaceutical composition of the present invention can be produced by treating these essential components and optional components according to a conventional method.
[0009]
【Example】
Hereinafter, the present invention will be described in more detail with reference to examples, but it is needless to say that the present invention is not limited to such examples.
[0010]
<Example 1>
According to the formulation shown below, the pharmaceutical composition of the present invention was prepared. That is, the formulation components were solubilized with stirring at room temperature to obtain the pharmaceutical composition of the present invention.
Ethylcellulose 4 parts by weight Water 4 parts by weight Diisopropyl adipate 9 parts by weight Terbinafine hydrochloride 5 parts by weight Ethanol 78 parts by weight <Example 2>
According to the formulation shown below, the pharmaceutical composition of the present invention was prepared. That is, the formulation components were solubilized with stirring at room temperature to obtain the pharmaceutical composition of the present invention.
Ethylcellulose 3.5 parts by weight Methacrylic acid / methyl methacrylate copolymer 0.5 parts by weight Water 4 parts by weight Diisopropyl adipate 9 parts by weight Terbinafine hydrochloride 5 parts by weight Ethanol 78 parts by weight
<Example 3>
Using the above-mentioned external preparation for skin of the present invention, the effect on the onychomycosis model was examined. That is, 15 g of Bacto agar was added to 1 liter of salt medium to prepare an agar salt medium, sterilized by autoclave, cooled to 45 ° C., and spore suspension obtained by slant culture had 1 × 10 6 conidia counts. The solution was adjusted to be / ml, and 2 ml was gently dispensed into a 90 ml petri dish. The solidification of the agar was confirmed, and a silicone rubber adhesive with a Teflon O-ring adhered to a human nail was placed in the center of the medium and infected for 5 days. After infection, 5 μl of the pharmaceutical composition of Example 1 was charged into a Teflon O-ring. The state of the mycelium growing between the nail and the agar medium over time after the addition of the drug was visually observed according to the following criteria. As a comparative example, the same operation was carried out using Comparative Example 1 in which terbinafine hydrochloride in Example 2 was replaced with amorolfine hydrochloride in Comparative Example 1, and Comparative Example 2 in which clotrimazole was replaced. The average score in 4 cases is shown in Table 1. From this, it is clear that the pharmaceutical composition of the present invention has an excellent effect on onychomycosis.
Observation criteria: Score 3: Bacterial growth was observed, Score 2: No change from the time of drug addition, Score 1: Bacterial decrease was observed, Score 0.5: Bacterial presence was slightly observed, Score 0: Bacteria became negative [0012]
[Table 1]
[0013]
【Effect of the invention】
According to the present invention, it is possible to provide a pharmaceutical composition suitable for antimycosis and onychomycosis.
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JP2000241953A JP4899139B2 (en) | 2000-08-10 | 2000-08-10 | Antifungal pharmaceutical composition |
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JP2000241953A JP4899139B2 (en) | 2000-08-10 | 2000-08-10 | Antifungal pharmaceutical composition |
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GB0103046D0 (en) | 2001-02-07 | 2001-03-21 | Novartis Ag | Organic Compounds |
JPWO2003105903A1 (en) * | 2002-06-18 | 2005-10-13 | ポーラ化成工業株式会社 | Antifungal pharmaceutical composition |
DE602004021253D1 (en) * | 2003-03-21 | 2009-07-09 | Nexmed Holdings Inc | ANTIMYCOTIC NAIL POLISH AND APPLICATION METHOD |
JP2005029502A (en) * | 2003-07-11 | 2005-02-03 | Taisho Pharmaceut Co Ltd | Antifungal agent composition |
JP5059408B2 (en) * | 2004-08-05 | 2012-10-24 | 久光製薬株式会社 | Nail preparation |
EP1827401A2 (en) * | 2004-12-10 | 2007-09-05 | Talima Therapeutics, Inc. | Compositions and methods for treating conditions of the nail unit |
CA2623031C (en) * | 2005-09-29 | 2014-05-13 | Novartis Ag | Antifungal composition |
US8697753B1 (en) | 2013-02-07 | 2014-04-15 | Polichem Sa | Method of treating onychomycosis |
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JPH10330247A (en) * | 1997-06-02 | 1998-12-15 | Pola Chem Ind Inc | Plaster for nail |
US6231875B1 (en) * | 1998-03-31 | 2001-05-15 | Johnson & Johnson Consumer Companies, Inc. | Acidified composition for topical treatment of nail and skin conditions |
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